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 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.

The discussion on a proposed quality similarity assessment criteria of rituximab biosimilar / 药学学报

Recently, biosimilar antibodies have become a mainstream component of the biopharmaceutical industry in China. The principle requirements for the development and evaluation of biosimilars are based on proving similarity in product quality (analytical similarity) between a proposed biosimilar candidate and the originator reference drug. However, because the quality of a reference drug often varies during the life cycle and not all reference drug samples are able to collected by a biosimilar sponsor, it has not been practical to accurately determine the critical quality attributes as well as an accurate control range through the characterization of the limited number of reference drug lots that are typically collected. Therefore, the development and evaluation of biosimilars has been challenging both for industry and regulatory agencies. In this article, The Chemistry, Manufacturing and Control (CMC) dossier of the rituximab originator company and the dossiers of 18 biosimilar companieswere retrospectively analyzed. Furthermore, the assessment criteria to determine quality similarity of rituximab biosimilar candidates have been proposed, which criteria have been used by reviewing the physicochemical and biological properties data obtained from 123 lots of the reference drug. Moreover, some case studies have been provided that illustrate the application of the proposed analytical similarity criteria in the practice of drug evaluation.

Research progress, chemistry, manufacturing and controlsconsiderations of mesenchymal stem cell products / 药学学报

The number of clinical trials for mesenchymal stem cell (MSC) products ranked the top among all stem cell products, with more than 900 trials ongoing or completed by 2018. In China, many MSC clinical trials have started as "the third type of medical technique" and the dossiers of MSC products have been submitted to National Medical Products Administration (NMPA). The biological function and therapeutic effect of MSCs are constantly being recognized in scientific communities. However, the observed functions of MSCs in vitro are not fully reproduced in the living microenvironment in vivo. There are substantial variations among tissue origins, cellular phenotypes and biological functions. Different formulations, delivery methods, manufacture processes or doses all greatly affect the clinical efficacy. It is difficult for MSCs to maintain the naive state due to the differences between in vitro culture conditions and in vivo microenvironment. Meanwhile, there is no widely accepted scientific definition for MSCs until now, due to the complexity of manufacturing process and variable sources. Consequently, the regulation of MSC products is a challenge for drug administrative agencies. In this article, we review the research progress of MSC products around the world, and summarize the considerations in evaluating the chemistry, manufacturing and controls (CMC) section of MSC product applications, with respect to raw materials, manufacture processes and quality control. We hope that the information summarized here will provide insights for the development and evaluation of MSC 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.

Biosimilarity Study Regarding Product Quality of Candidate Recombinant Monoclonal Antibodies as Biosimilars / 中国药学杂志

OBJECTIVE: Nowadays, recombinant monoclonal antibodies developed as biosimilar domains in application category for Investigational New Drug in domestic. The quality similarity should be prequalified for candidate drug to be developed as biosimilar. Here, the concept of quality biosimilarity was proposed and discussed from reviewer as well as developer. METHODS: The challenge of developing and evaluating biosimilar antibodies was emphasized. Then, the domestic sponsor's common problems were sorted out and critical quality attributes of some originator antibodies were summarized. Lastly, the reasons of holding letter or case rejected were exemplified and analyzed. RESULTS: AND CONCLUSION: The sponsor are encouraged to conduct comparing exercise by state-of-art analytical technologies to conform the quality similarity between a proposed biosimilar antibody and the originator product, the reviewers should also be very cautious to assess quality differences. Joint efforts and effective communication from researcher and reviewer are critical for promoting development of domestic biosimilar and addressing the unmet medicine need.

Research and development of innovative antibody-based drugs / 药学学报

With the development of antibody manufacturing technology and improvement in new drug research and development (R&D) capabilities in domestic industry, more and more innovative antibody-based drugs were registered at the Investigational New Drug (IND). This type of drugs could be divided into three categories:new sequence antibodies (biobetter or new target antibodies), bispecific antibodies (or antibody cocktails), and antibody drug conjugates. Comparing with biosimilar antibodies, the innovative antibodies R&D was characterized by some significant features including "innovation", "clinical phase-appropriate" and "progressing". The minimum requirements of Chemical, Manufacturing and Control (CMC) content for innovative antibodies were obviously different from biosimilar antibodies. Here, the recent progress of antibody engineering and IND date of innovative antibodies in domestic are summarized. The general regulatory requirement and special considerations for representative innovative antibodies were proposed. Some common problems concerning innovative antibodies R&D are discussed.

Relationship between placental pathology and small-for-gestational age neonates / 中华病理学杂志

<p><b>OBJECTIVE</b>To investigate the relationship between pathological abnormalities of placenta and small-for-gestational-age neonates.</p><p><b>METHODS</b>One hundred placentas of small-for-gestational-age (SGA group) and 200 appropriate-for-gestational-age (AGA group) with single living birth in third trimester were investigated by gross and microscopic examination. The AGA placentas were collected from 2 cases following every SGA placenta. All cases were collected from Shanghai Changning District Maternity and Infant Health Hospital from January 2010 to December 2011.</p><p><b>RESULTS</b>The gestational week, neonatal birth weight, full-term neonatal birth weight, the preterm birth rate and vaginal spontaneous delivery rate were significantly lower in SGA group than that in AGA group (P < 0.002). Full-term placental volume, placental weight and fetal placental weight ratio were lower in SGA group than that in AGA group (P < 0.05). Unusual insertion and torsion of umbilical cord were more common in SGA group (P < 0.05). Syncytial knots increase, avascular villi and villous infarcts were significantly higher in SGA group (P < 0.005), but there were no significant difference between SGA group and AGA group in intervillous thrombi, chronic villitis and chorangiosis (P > 0.05). Gestational hypertension disease and abnormality of fetal monitoring were more common in SGA group (P < 0.05).</p><p><b>CONCLUSIONS</b>Gestational hypertension disease is the main clinical cause of SGA. Some placental abnormality can affect the growth and development of intrauterine fetus.</p>

The Changes of Glutathione and Ergosterol in Saccharomyces cerevisiae Under High Pressure / 中国生物工程杂志

The growth changes of glutathione (GSH) and ergosterol in Saccharomyces cerevisiae (CICC1447 and CICC1339) were detected under 0.5Mpa pressure with compressed high-pure air (O-2∶N-2=21∶79). The results showed that logarithmic phases of the two strains were delayed; their biomass and special growth rate were lower than those of control sample (0.1MPa) and the double time were prolonged under 0.5MPa. High-pressure could increase the content of GSH obviously, compared to ambient atmosphere control samples. When the holding time was 3h, the content of GSH and ergosterol in CICC1447 increased 42.6% and 20.1%, respectively. However, the content of GSH in CICC1339 increased 58.7% when the holding time was 6h, while ergosterol content reduced. The results indicated that different yeast strains have different stress-response mechanism to copy with high-pressure shock.