Batch release

Chemical development Proof of structure and configuration are required as part of the information on chemical development. The methods used at batch release should be validated to guarantee the identity and purity of the substance. It should be established whether a drug produced as a racemate is a true racemate or a conglomerate by investigating physical parameters such as melting point, solubility and crystal properties. The physicochemical properties of the drug substance should be characterized, e.g. crystallinity, polymorphism and rate of dissolution. 

Annex 16 Certification by a Qualified person and Batch Release Annex 17 Parametric Release... 

This system assures overall compliance with cGMPs and internal procedures and specifications. The system includes the quality control unit and all of its review and approval duties (e.g. change control, reprocessing, batch release, annual record review, validation protocols, and reports, etc.). It includes all product defect evaluations and evaluation of returned and salvaged drug products. 

Activities Carried out Manufacture of active substance Manufacture of finished product Manufacture of intermediate or bulk Q Packaging only Importing Laboratory testing Batch control and batch release Storage and distribution Investigational medicinal products Other ... 

For an example of a control chart see Fig. 1.31 and Sections 4.1 and 4.8. Control charts have a grave weakness the number of available data points must be relatively high in order to be able to claim statistical control . As is often the case in this age of increasingly shorter product life cyeles, decisions will have to be made on the basis of a few batch release measurements the link between them and the more numerous in-process controls is not necessarily straight-forward, especially if IPC uses simple tests (e.g. absorption, conductivity) and release tests are complex (e.g. HPLC, crystal size). 

As long as the health authorities accept 90-110% specification limits on the drug assay, the normalization method presented above will barely suffice for batch release purposes. Since there is a general trend toward tightening the specification limits to 95-105% (this has to do with the availability of improved instrumentation and a world-wide acceptance of GMP-standards), a move toward options 1 (HPLC) and 2 (DA-UV) above is inevitable. 

A pharmaceutical specialty is produced in three dosage strengths (major component A) A and a second component B are controlled by HPLC for batch release purposes. It is decided to replace the manual injection of the sample solution by an automatic one. It is expected the means will remain the same but the standard deviations will be smaller for the automatic injection. Cross-validation of the methods is effected by running both methods on each of 10 samples. The mean and the standard deviation for each series of 10 measurements is given in Table 4.19. 

Once a product gains FDA approval for marketing, the sponsor should maintain a readily retrievable profile of commercial batches. This includes individual batch release data and stability data. These data should be compiled throughout the year and tabulated prior to the anniversary of NDA approval for submission in the annual product report to FDA. By maintaining an ongoing database, which is reviewed as new information is added, changing trends in the data can be observed and management notified if any of these trends are unfavorable. 

Details of the specific types of apparatus need not normally be given except for nonstandard processes. A flow chart of the manufacturing operation and the in-process controls (and acceptance limits) is required. Proposals for alternative processes will need to be supported by appropriate data to show that the finished products resulting from these are consistent with the finished product specification. Certain manufacturing operations such as mixing may require additional information on quality parameters monitored during production and prior to batch release. Appropriate quality parameters should be included in the finished product specification regardless of the outcome of validation studies (e.g., content uniformity for solid and semi-solid products). 

Another use, now almost abandoned except for in natural product-derived chugs, is in quality control testing or batch release testing. The latter was once a mandated part of the standardization process for antibiotics, digoxin and insulin in the U.S. 

Several in vitro tests are currently employed to assure drug product quality. These include purity, potency, assay, content uniformity, and dissolution specifications. For a pharmaceutical product to be consistently effective, it must meet all of its quality test criteria. When used as a QC test, the in vitro dissolution test provides information for marketing authorization. The dissolution test forms the basis for setting specifications (test, methodology, acceptance criteria) to allow batch release into the market place. Dissolution tests also provides a useful check on a number of physical characteristics, including particle size distribution, crystal form, etc., which may be influenced by the manufacturing procedure. In vitro dissolution tests and QC specifications should be based on the in vitro performance of the test batches used in in vivo studies or on suitable compendial specifications. For conventional-release products, a single-point dissolution... 

Quality System This consists of procedures and specifications to assure the overall compliance for the facility. Quality control, change control, batch release, internal audits, and quality records are part of the quality system. 

Common technical specifications (CTS) are to be adopted by the Article 7.2 Committee (a working group of scientific experts appointed by the Member States) which will apply to devices in Annex II List A and, when required, devices in Annex II List B. There is some uncertainty about the circumstances in which the requirement might apply to List B devices. CTS establish appropriate performance evaluation and re-evaluation criteria, batch release criteria, reference methods, and reference materials. If, for duly justified reasons, manufacturers do not comply with the CTS, they must adopt other solutions which are at least equivalent to these specifications. CTS are intended mainly for the evaluation of the safety of the blood supply and organ donations. 

Insofar as the provisions laid down in (a), (b) or (c) are complied with, investigational medicinal products shall not have to undergo any further checks if they are imported into another Member State together with batch release certification signed by the qualified person. 

The sample is to be tested immediately upon receipt if the test is a requirement for batch release. If the test is not a requirement of batch release, the sample may stored at 2 to 8°C for up to 24 hours however, the sample shall then be vortexed for 30 minutes prior to test. 

Annex 16 Certification by a qualified person and batch release... 

Although the PIC/S GMP guide is harmonized with the EU GMP code and their contents are similar, there are some minor differences between them. Instead of the term qualified person, the PIC/S GMP guide uses the term authorized person. Furthermore, all references to EU directives have been deleted from the PIC/S GMP guide. Moreover, PIC/S has not adopted Annexes 16 and 18 of the EU GMP code. Annex 16 is specific to the EU GMP code covering the status of a qualified person in batch release and Annex 18 is the ICH GMP guide for the manufacture of APIs, which the PIC/S Committee has adopted as a stand-alone document (PE 007)... 

Despite the fact that the operating characteristic (OC) curve of the USP (905) test guarantees a significant portion of each batch will have poor quality before batch rejection is probable [42,43], companies have become comfortable with their odds. Process analytical monitoring tools such as NIR spectroscopy, which are capable of high-speed sampling in line, online, or at line, have been perceived as an additional burden on the rate of successful batch release. 

The ambiguity in the revised (CPG) regulations may seem to signify that manufacturers would need to undertake even more extensive validation exercises when in fact the CPG contains language providing a pathway for batch release to market distribution concurrent with the manufacture of initial conformance batches or with a single conformance batch [57] ... 

Directed toward reduced inventories, lower numbers of batch failures, and efficient batch release (QA/QC). 

The design of the validation testing and the composition of the protocol reflect the circumstances under which the study is conducted. For retrospective validation the test may be statistical analysis of batch release data, such as assay, pH, physical appearance, residual moisture, reconstitution time, and constituted solution appearance. This retrospective process validation would be intended to demonstrate that the product is of consistent quality. A critical review of the processing conditions in a retrospective validation may consist of a test comparing actual processing conditions during lyophilization with ideal parameters. This not only shows adherence to the defined processing conditions, but also demonstrates process reproducibility. 

GMP risk assessment Qualified/trained resource System life-cycle validation System environment Current specifications Software quality assurance Formal testing/acceptance Data entry authorization Data plausibility checks Communication diagnostics Access security Batch release authority Formal procedures/contracts Change control Electronic data hardcopy Secure data storage Contingency/recovery plans Maintenance plans/records... 

In cases in which there is no laboratory error clearly identified, there is no scientific basis for invalidation of the original test results. The guidance recommends that all results, both passing and suspect, be reported and considered in batch release decisions. 

The job of the investigation team is to scrutinize all nonlaboratory aspects of the batch process for a possible cause. For a stability study, the batch record takes on less importance since the executed record has already been audited through the batch release process. The aberrant result may have evolved over time or be the result of sampling, analytical, or process irregularities. Some other possible causes of aberrant results include the following ... 

Dissolution testing is also used to assess batch-to-batch quality, where the dissolution tests, with defined procedures and acceptance criteria, are used to allow batch release. Dissolution testing is also used to (1) provide process... 

Examples of GxP processes (functions) include supplier management, procurement, goods receipt, materials management, production control, quality control, batch release, distribution, recall, customer complaints, batch tracking, and compliance management (e.g., SOP management, electronic data archiving). 

European Union, Annex 16 — Certification by a Qualified Person and Batch Release, European Union Guide to Directive 91/356/EEC. 

Criticality GxP functionality Analytical results Batch release and recall... 

Once the business processes have been agreed, a GxP assessment can be conducted. This should address those operational aspects of the system that impact the quality of finished pharmaceutical products and will include supplier details, batch records, laboratory quality control records, batch release, and recall. An example of a GxP impacting functionality in an MRP 11 system is given in Appendix 35F. Experience suggests that perhaps between 25 to 50% of MRP 11 functionality is GxP critical. The GxP operational aspects will form a focal point during any GxP regulatory... 

Successful batch release in live environment Number of new change reqnests Number of outstanding change reqnests Number of help desk calls Changes to bnsiness processes Data accuracy... 

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