Statistical process control of manufacturing tablets for antiretroviral therapy

Abstract In this study, the manufacturing process of lamivudine (3TC) and zidovudine (AZT) tablets (150+300 mg respectively) was evaluated using statistical process control (SPC) tools. These medicines are manufactured by the Fundação para o Remédio Popular "Chopin Tavares de Lima" (FURP) laboratory, and are distributed free of charge to patients infected with HIV by the Ministry of Health DST/AIDS national program. Data of 529 batches manufactured from 2012 to 2015 were collected. The critical quality attributes of weight variation, uniformity of dosage units, and dissolution were evaluated. Process stability was assessed using control charts, and the capability indices Cp, Cpk, Pp, and Ppk (process capability; process capability adjusted for non-centered distribution; potential or global capability of the process; and potential process capability adjusted for non-centered distribution, respectively) were evaluated. 3TC dissolution data from 2013 revealed a non-centered process and lack of consistency compared to the other years, showing Cpk and Ppk lower than 1.0 and the chance of failure of 2,483 in 1,000,000 tablets. Dissolution data from 2015 showed process improvement, revealed by Cpk and Ppk equal to 2.19 and 1.99, respectively. Overall, the control charts and capability indices showed the variability of the process and special causes. Additionally, it was possible to point out the opportunities for process changes, which are fundamental for understanding and supporting a continuous improvement environment.

Effect of human immunoglobulin manufacturing process on polymer content / 中国输血杂志

【Objective】 To investigate the changing pattern of polymer content in the manufacturing process of human immunoglobulin, especially the correlation between pH value and polymer content, so as to provide basis for the control of polymer in human immunoglobulin products. 【Methods】 IVIG and HBIG low pH intermediate samples were taken and their pH values were adjusted to different gradients with 0.5 or 0.1 mol/L HCl. The polymer content was detected by HPLC, and the influence of different pH values on polymer content was observed and analyzed. 【Results】 With low pH value, the polymer content of samples increased from <1% to 10% with the decrease of pH value. When pH value was in the range of 3.85~3.10, the polymer content in the samples increased from 0.38% to 15.5% exponentially with the decrease of pH value. The logarithm of polymer was linearly correlated with pH value. 【Conclusion】 When pH value is low, polymer content of human immunoglobulin is significantly affected by pH value. Keeping pH value above 4.0 during the whole manufacturing process of human immunoglobulin is suggested.

Chemistry, manufacturing and control considerations of rAAV-based gene therapy products / 药学学报

Recombinant adeno-associated virus (rAAV)-based vector has shown great promise for human gene therapy, due to its advantage in eliciting long-term transgene expression, absence of adverse effect, infection ability to both dividing and non-dividing cells, non-genomic integration, and low immunotoxity. To date, three AAV-based products have been authorized to enter European and American markets, and more than 200 rAAV-based candidates are in the process of clinic trails. Nevertheless, domestic industry is facing the challenge of manufacturing clinical grade rAAV vector, and regulatory agencies are lack of practical experience in assessing such products. Herein, this paper summarizes the latest research progress of rAAV-based gene therapy products, and discusses some quality assessment concerns in raw materials, manufacturing process and quality control, expecting to promote its clinical transformation and application.

Chemistry, manufacturing, and controls regulatory considerations for human pluripotent stem cell-derived cellular products / 药学学报

In recent years, the number of clinical trials of stem cell products has increased, and the research and development technology and evaluation system have developed rapidly. Human pluripotent stem cell (hPSC)-derived cellular products are in the phase I/II stage of clinical trials. Related products include hPSC-derived neurons, retinal pigment epithelial cells, pancreatic beta cells, etc. They are generally used for the repair and replacement of functional cells related to degenerative diseases and genetic diseases via local transplantation. So far, no similar products have been officially approved on market. As hPSC possesses multi-directional differentiation potential and the ability to form teratoma in vivo, compared with other stem cell products, hPSC-derived cellular products have relatively higher risk of tumorigenicity, longer differentiation induction cycle, more complex production process, together with the rapidly updating quality characterization methods, which pose challenges to the scientific evaluation of their human applications. Based on the problems in the recent review and communication of clinical trial applications of stem cell products, and with reference to the relevant technical guidelines, this paper proposes the chemistry, manufacturing, and controls review considerations on the manufacturing process and quality study of hPSC-derived cellular products. We hope to improve the communications between developers and regulators.

Research Progress of Enzyme Replacement Therapy for Rare Diseases Products and Their Pharmaceutical Assessment / 中国药学杂志

OBJECTIVE: To summarize the latest research progress in the development of enzyme replacement therapy drugs for rare diseases at home and abroad and their pharmaceutical assessment. METHODS: Based on the representative literature at home and abroad, this paper propose key points for consideration (such as molecular design, host selection, production process and quality control, etc.), as well as comments and suggestions for researcher of such products from review and evaluation perspective. RESULTS: Due to the complexity and heterogeneity of the drug molecules of enzyme replacement therapy for rare diseases, the quality research is the main difficulty in pharmaceutical development and evaluation. CONCLUSION: In recent years, in order to alleviate the lack of rare disease drugs in China and meet the urgent clinical needs, Chinese government has issued a series of policies to encourage the research and development of rare disease drugs.

Application prospect of new technology and new equipment in production of Chinese patent medicine / 中国中药杂志

At present,the production equipment and process of Chinese patent medicines still have many problems including high energy consumption,low efficiency,high pollution,and low intelligence,which seriously hinder the transformation,upgrading and modernized development of traditional Chinese medicine industry. With the emergence of various new pharmaceutical technologies and the application of technologies of other fields in traditional Chinese medicine industry,the development of Chinese patent medicine has ushered in new opportunities. The processes such as pulverization,mixing,extraction,separation,concentration,drying and sterilization are unique for the production of Chinese patent medicine. These main features can be distinguished from the manufacturing process of chemical drugs,determining the characteristics of the production process and equipment of Chinese patent medicine. In this paper,each operation unit was mentioned to summarize and analyze the new equipment and new technologies with advantages and characteristics in recent years from the perspectives of definition,principle,classification and application. Among them,the automatic spray device of the mixer,the extraction and separation equipment of volatile oil,and the crane basket-type circulation extraction technology,composite multi-layer spiral vibration countercurrent drying,and vibration sterilization equipment all have rapid development in recent years,with great prospects in the production of Chinese patent medicines. In this paper,we also analyzed some problems existing in the production equipment and technology of Chinese patent medicine and the key factors restricting the development of Chinese patent medicine,discussed the transformation of Chinese patent medicine production from traditional to modern and from semi-automatic to intelligent,and put forward three suggestions to help Chinese patent medicine achieve the goal of improving quality,efficiency and green manufacturing in production.

Chemistry, manufacturing and controls regulatory considerations for marketing authorization application of therapeutic antibody in China / 药学学报

The marketing authorization application is a milestone of drug life cycle, which indicates a candidate has potential to become a commercial drug. As of now, there are only 12 domestic therapeutic antibodies approved in China. The chemistry, manufacturing and controls (CMC) development and evaluation of monoclonal antibody were more challenging for both industry and authority agency. As the result of domestic biopharmaceutical industry development and implement of priority review system, the marketing authorization application of domestic antibody biosimilar and imported antibodies had dramatic increased in recent years. Thus, the CMC evaluation of monoclonal antibody become the important task of biological product's marketing authorization registration management. In the article, the CMC regulatory considerations for marketing authorization application based on author's review experience was proposed, in order to accelerate development and registration of commercial antibody in China.

Fabrication of additive manufacturing interim denture and comparison with conventional interim denture: A case report / 대한치과보철학회지

With development of digital dentistry, the 3-dimensional (3D) manufacturing industry using computer-aided design and computer-aided manufacturing (CAD/CAM) has grown dramatically in recent years. Denture fabrication using digital method is also increasing due to the recent development of digital technology in dentistry. The 3D manufacturing process can be categorized into 2 types: subtractive manufacturing (SM) and additive manufacturing (AM). SM, such as milling is based on cutting away from a solid block of materal. AM, such as 3D printing, is based on adding the material layer by layer. AM enables the fabrication of complex structures that are difficult to mill. In this case, additive manufacturing method was applied to the fabrication of the resin-based complete denture to a 80 year-old patient. During the follow-up periods, the denture using digital method has provided satisfactory results esthetically and functionally.

Application of Shewhart Control Charts in the Inspection of Pharmaceutical Manufacturing Process / 中国药师

Objective:Through the establishment of shewhart control chart,to grasp the variation of products and avoid the occur-rence of failures.Methods:According to the characteristics and control requirements of quality parameters,several types of typical pa-rameters were introduced to illustrate the detection results and create the control charts in order to confirm whether the production was under the control. Results:The analysis of control charts could expedite the operator discovering the process variation caused by spe-cial factors,and taking corrective/preventive actions so that the products consistently complied with the regulatory specifications and production instructions. Conclusion:Control charts can be used as a monitoring tool in pharmaceutical manufacturing process,which can reduce the reject ratio and promote the continuous improvement of products.

Regulatory perspective for chemistry manufacturing and controls considerations in chimeric antigen receptor-modified T cell therapy / 药学学报

As a living cell product, chimeric antigen receptor (CAR)-T cell therapy displays multiple characteristics including the diversity of raw materials, the complexity of manufacturing process and the complementarity of quality control set. Pharmaceutical research and evaluation of CAR-T cell therapy are fundamentally different from small molecule and macromolecular recombinant proteins. Chemistry manufacturing and controls (CMC) review of investigational new drug (IND) submission for CAR-T therapy should especially pay attention to above unique characteristics and focus on potential risks to ensure clinical safety. Based on questions and concerns from recent CMC review practice and workshop on CAR-T cell therapy IND application, the critical points to consider for CMC study is proposed, and questions related to supplementation are also discussed in this review to accelerate the clinic translation of CAR-T therapy.

Comprehensive analysis on "toxicity and effect" of Chinese pharmaceutical preparations / 中国中药杂志

The manufacturing process of Chinese medicines is the significant link to achieve "effect-enhancing and toxicity-reducing", including an interaction between "toxicity and effect". This paper would elucidate the effects of Chinese herbal compound decoction, preparation, dosage forms, route of administration and quality of pharmaceutical excipients on "toxicity-effect" theory from the formulation approaches. The article pointed out that the comprehensive analysis on "toxicity-effect" theory should be strengthened from the aspects of overall manufacturing, fundamental research and modern Chinese preparation, to explore the mechanism of "effect-enhancing and toxicity-reducing" in the manufacturing process, clarify the core status of Chinese preparation in "toxicity-effect" theory, and ensure the security and effectiveness in traditional Chinese medicine clinical application.

A Comparison of the Humoral Immune Response Induced by a Recombinant Human Protein in Wild Type Mice and in Transgenic Mice Expressing the Protein.

Aim: The aim of this work was to investigate the correlation between anti drug antibody (ADA) induction and how different manufacturing processes of biopharmaceuticals affect the immunogenicity of the protein. This was done by testing four different batches of the same recombinant human protein in transgenic (Tg) mice. Methodology: Wild type (Wt) and human protein-transgenic (Tg) mice were challenged by repeated subcutaneous injections of four batches of a drug candidate protein, obtained by different purification methods. Differences between drug-specific IgG1, IgG2a, IgG2b, IgG3 and IgM antibody patterns produced in Tg vs. Wt mice were investigated and compared to the plasma cytokine profiles. A conventional ELISA was used as a reference method for ADA detection. Results: ADA responses detected in Tg mice were mainly of the IgG1 subclass and occurred only in significant response to the batch containing the highest level of proteins originating from the recombinant host cells. Wt mice, on the other hand, showed a combined IgG1/IgG2b response to all drug batches, except to the batch with the highest purity. The most pure batch failed to induce significant ADA in both Wt and Tg animals, suggesting host cell derived impurities to be a strong contributing factor to the antibody responses observed. Conclusion: Thus, an isolated IgG1 response in drug-tolerant Tg mice may serve as a potential biomarker of an immunological reaction to process-related impurities of the protein drug. In contrast, a combined IgG1/IgG2b-profile, as observed in immunoreactive Wt mice, more likely reflects a xeno-response.

A Case of Lead Poisoning by Ingesting Herbal Pills Tainted by Lead during the Manufacturing Process / 대한산업의학회지

BACKGROUND: This is a case report of lead poisoning after herbal pill ingestion. We report this case here as a reminder that contamination during the manufacturing process is an important issue regarding herbal pills. Case Report: A 37-year-old male was admitted to the hospital with abdominal pain caused by cholecystitis. He was transferred to the Department of Occupational and Environmental Medicine on 26 December 2008, because of anemia. On follow-up examination post cholecystectomy, the patient had increasing blood lead levels. There was no specific finding in his medical history, but he had been taking herbal pills for 3 months to treat dyspepsia. We performed an analysis on the herbal pills, and determined a lead concentration of 1485 mg/kg. When he was admitted to the hospital, the patient had a blood lead level of 84.13 microgram/dL and a zinc protoporphyrin level was 230 microgram/dL. The patient was treated with 250 mg of Penicillamine, 4 times per day. During follow-up 3 weeks later, the patient's blood lead level had been reduced to 36.52 microgram/dL which allowed us to take him off of Penicillamine. By 7 months follow-up, the patient's blood lead concentration had fallen from 36.52 microgram/dL to 20.93 microgram/dL. CONCLUSION: Lead poisoning was confirmed by analyzing blood lead levels and the cause was herbal pills. Upon analysis of the herbal pills, we have discovered that the herbal pills contained an amount of lead acquired during the manufacturing process, based on the high levels of this heavy metal in comparison to other metals. Private herbal pill manufacturing plants need systematic management and oversight.