Xu Wenjun

Jinhua Jumei Network Technology Co.,Ltd.,China

May 23rd,2023,Center for Medical Device Evaluation,National Medical Products Administration introduced Guidelines for the Registration and Review of Recombinant Collagen Wound Dressings(hereinafter referred to as Wound Dressings Guidelines) and Guidelines for Raw Material Evaluation of Recombinant Humanized Collagen(hereinafter referred to as Raw Material Guidelines),which could better standardize the management of the raw material of recombinant collagen and wound dressings.It is worth mentioning that Raw Material Guidelines mainly offers the evaluation methods concerning the raw material of recombinant humanized collagen used by medical devices.Currently,in the medical beauty and cosmetics industry,many products adopt recombinant humanized collagen.These two guiding principles exert an effect on standardizing medical beauty device products,and also have a certain guiding significance for cosmetics added with recombinant humanized collagen.

Protein structure,biological function and stability test are based on law

Raw Material Guidelines involve preface,evaluation key points and references.According to its preface,the humanized collagen mentioned in this document refers to “the full length or partial amino acid sequence fragment encoded by a specific type of human collagen gene prepared by DNA recombination technology,or a combination of functional fragments of human collagen.”

Compared with another two types of collagen in Guidelines for Raw Material Evaluation of Recombinant Humanized Collagen,this is the most common collagen in the field of medical beauty and cosmetics.Based on the key points of evaluation described by Raw Material Guidelines,the evaluation and method references have been provided covering the study on the function of recombinant humanized collagen,biological risk assessment of materials,stability research as well as direct-contact vessels/material studies.In terms of cosmetics industry,the author summarized three aspects for readers as follows.First,as for the function study,the document pointed out that for raw materials,necessary identification,purity and impurity analysis shall be carried out with reference to relevant industrial standards.Also,various analysis methods could be adopted to identify the molecular weight,isoelectric point,amino acid sequence as well as posttranslational modification of raw materials so as to make sure if the final product enjoys the claimed conformation,aggregation state,degradation state of raw materials and advanced structure of collagen.As is known to us all,the biological activity or function of protein is closely related to its structure,so the structural characteristics of recombinant humanized collagen have an important influence on its activity.

The Raw Material Guidelines also offers some references regarding the test analysis of structural characterization,such as that of triple helix structure analysis and fiber quality/porous and reticulated one.

Regarding the biological function assessment,the Raw Material Guidelines mentioned that “we can reevaluate the biological function of recombinant and humanized collagen by taking advantage of the interaction between cell and collagen.Evaluation methods of cell proliferation,differentiation,adhesion,transfer or migration can be referred to YY/T 1849 Recombinant Collagen.” “We need to test the interaction between materials and cells as well as the function of guiding cells.Parameters of cell response include cell morphology,area,and volume,which can be evaluated visually by two-dimensional (2D) or three-dimensional(3D) imaging techniques,as well as survival,proliferation,programmed apoptosis and migration.”

Stability of collagen is also the priority during the production.According to the document.

Dressings couldn’t be absorbed by human body and names should be unified

Wound Dressings Guidelines mainly involve scope of application and key points of registration review.It is clearly indicated that “these guidelines apply to recombinant collagen wound dressings managed under Category II medical devices,whose structural composition contains recombinant collagen components (excluding collagen extracted from animal tissues) for the care of non-chronic wounds and their surrounding skin.The ingredients contained in the product do not have pharmacological effects and cannot be absorbed by the human body.If the product classification and attribute are unclear,the product classification and attribute definition shall be applied for.”

The inspection priorities include supervision information,review,non-clinical data,clinical evaluation data,product specifications as well as label samples.In addition,we should pay attention to the following aspects.First,the material of the product name is “recombinant collagen” such as recombinant collagen gel dressing,recombinant collagen wound application.The product name does not distinguish the specific material characteristics unless there is sufficient evidence showing that the structural characteristics of the recombinant collagen raw materials can bring additional benefits to the declared product function;based on the product description of the review,the guidelines specify both the product composition and the model specification.

Composition: The declared products include recombinant collagen ingredients,film forming ingredients or thickening component of polymer,moisturizing and lubricating ingredients,conditioning agent,emulgator,corrosion prevention ingredients,buffer agent,solvent,matrix carrier,etc.Apart from recombinant collagen ingredients,there are other common ingredients including polyvinyl alcohol,polyethylene glycol,carbomer,xanthan gum,sodium alga acid,carboxyl methyl cellulose,glycerinum,propylene glycol,trehalose,polyvinylpyrrolidone(PVP),triethanolamine,Sorbitan Oleate (span 80),cetostearyl alcohol,sodium methylparaben,phenoxyethanol,methylparaben,acetate buffer,phosphate buffer,water for injection,purified water,and non-woven paste as well.These products are often in the form of gel,liquid,application,and paste.They are single-use or can be used multiple times after unpacking.The products are provided in a sterile or non-sterile way.

Size: The differences regarding various sizes should be clarified in terms of the declared products with more than one specification.We should adopt correlation table or photos and graphs with descriptive texts so as to describe the composition,function,product features and technology parameters,etc.We should describe all types/specifications of products in a clear and accurate way such as 5 mL,10 g,15 mL/bottle and 25 g/paste.“The customized type can be provided based on customer needs” shall not appear.Any misleading information or content beyond the product description and predicted usage shall appear.

New rules regarding recombinant collagen introduced amid rapid development of the industry

In recent years,recombinant collagen emerged with synthetic biology in the industry of medical beauty and cosmetics.Many believe that recombinant collagen would become the phenomenal raw material next to hyaluronic acid.According to the data prediction of Frost &Sullivan,between 2022 and 2027,the market size of China’s recombinant collagen products will increase from 18.5 billion yuan to 108.3 billion yuan with a compound annual growth rate of 42.4%.Thanks to the expanding market,more businesses will join the game.Giant Biogene and Shanxi Jinbo Biopharmaceutical Ltd.started earlier while Bloomage Biotech regarded collagen as the second most strategic bio-active substance second to hyaluronic acid.

As the market expands along with more participants,the industry would inevitably meet with false advertising and concept addition.In order to further standardize the collagen market,National Medical Products Administration promulgated some relevant regulations in the past two years,stipulating the naming,product supervision and management as well as quality control of recombinant collagen biomaterials.

In March,2021,National Medical Products Ad mi nist ration published Guideli nes for Nome nclat u re of Recombinant Collagen Biomaterials which mentioned that the name of the biological material was comprised of core word and characteristic word.It was compiled in accordance with “characteristic word (if any)+core word(A+B)”.

On January 13rd,2022,National Medical Products Administration introduced the industrial standard of Recombinant Collagen (YY/T 1849-2022) and was officially operated since August 1st,2022.This standard specified the quality control requirements,detection indexes and detection methods of recombinant collagen,and was applicable to the quality control of recombinant collagen as raw materials for medical devices.

On January 28th,2023,National Medical Products Administration announced that YY/T 1888-2023 Guidelines for Raw Material Evaluation of Recombinant Humanized Collagen,the medical equipment industrial standard was approved and would be implemented on July 20th,2023.

With the release of such two guiding documents,it is clear that our supervisory departments are paying more attention to the subdivision and improvement of the rules in the field of recombinant collagen.It also reflects that domestic enterprises are stepping up efforts in the research and development in such area.There will be more scenarios where recombinant collagen can be used.

In the near future,the development of recombinant collagen industry tends to be standardized,but it also means that the industrial threshold is becoming higher and higher.