In recent years, China's implementation of the MAH system has also directly encouraged new drug innovation. China's biopharmaceutical innovation is in full swing, and nearly 3000 biotech companies are gradually moving towards becoming "B certificate holders" with the continuous promotion of R & D projects. Mah commissioned cdmo (R & D + production) has become an irresistible trend. MAH commissioned production will likely become the "next outlet" for the rapid development of China's pharmaceutical industry!
Here are some important links in the cooperation process between MAH and cdmo:
01 Safety audit
Cdmo is called "contract R & D and production organization", and it is also a drug commissioned R & D and production enterprise. Whether it is a R & D laboratory, a production plant or a production workshop, "safety first", and safety is the lifeline of an enterprise. Mah should always put safety first in the audit of cdmo enterprises. When MAH audits that there are potential safety hazards in cdmo R & D laboratory, it will also put forward to let it rectify. After all, there is no basis for entrustment without safety. Once the R & D data is lost due to safety factors such as fire, the entrusted R & D projects and huge investment will also be "washed away"; If the production plants and workshops of cdmo enterprises also have major hidden dangers of safety, environmental protection and occupational health (EHS), they may be punished by relevant national departments, resulting in shutdown or even bankruptcy. MAH will also be unable to provide stable supplies, and the enterprise will lose more than the gain.
02 Quality audit
Quality audit is a key step to determine whether MAH and cdmo cooperate. Mah and cdmo have three capability states. First, MAH and cdmo are strong. The systems of both sides are sound, and the combination of strong and strong is the most guarantee for the quality of drugs; Second, MAH is strong and cdmo is weak. For example, some large enterprises with a certificate scale entrust cro R & D institutions to develop new products; Third, MAH and cdmo are weak, so the quality of commissioned products is worrying. The level of quality audit also fully reflects whether MAH can supervise the level of cdmo.
The first kind of MAH is strong and cdmo is strong. Both parties can have a lot of business and learn from each other, but it is ultimately up to MAH to make decisions. After all, MAH is the first person responsible for product accidents; Second, MAH is strong and cdmo is weak. MAH can fully find problems through audit, either not this cdmo, or help it improve its level to achieve controllable entrusted product quality; The third kind of MAH weakness and cdmo weakness can invite competent third parties to improve the supervision level of MAH and the implementation level of cdmo's entrusted quality system.
In September 2021, FDA also issued a warning letter to a local enterprise because of the adverse supervision of cdmo. In mid April, FDA inspected the circle laboratory and found that it lacked appropriate supervision and procedures to manage the cdmo for the production, packaging and distribution of drugs. The cdmo failed to review the batch production records for the release of each batch of ready products as required, and also changed the labels of drug products recalled due to the handling of consumer complaints. The FDA warning letter reminded the circle Laboratory of the "insufficient supervision" of cdmo, They should be "ultimately responsible for the cGMP activities they perform".
03 R & D Capability and capacity matching
When MAH cooperates with a cdmo, it is often that this cdmo has a strong R & D ability to develop such products and has advantages over others. For example, MAH directly purchases the products of the cdmo pipeline under development, or cdmo specializes in a cutting-edge target, or develops a certain kind of disease treatment drugs that adapt to the MAH sales pipeline, or innovative drugs, me too drugs, generic drugs and other categories, as well as cdmo in microspheres, liposomes, nanocrystals In short, the R & D capability and strength of cdmo also determine the depth and length of cooperation between MAH and cdmo. "Without diamond, I dare not undertake the research and development of porcelain."
Another reason why MAH and cdmo can cooperate is the full matching of product capacity and cost advantage. Cdmo has to have a production workshop (production line) for the production of this product. After evaluation, it can be produced in line. If it is an active ingredient with a higher OEB level, it is possible that cdmo has a matching isolator. If the preparation cannot be in line, such as sterile injection or freeze-drying needle, whether it can be evaluated to use a disposable solution preparation bag, two sets of sub packaging equipment, etc. If the output is particularly large or the varieties are intensively purchased in the future, it is also necessary to evaluate whether cdmo has enough capacity for MAH. From the perspective of insurance supply, when MAH and cdmo sign the R & D cooperation agreement, they should specify in the agreement how cdmo will guarantee the commercial capacity in the future, such as how much capacity it promises to vacate or how many production lines it will build to meet the future volume needs of MAH products. Of course, in the era when China is paid by national medical insurance funds, how to achieve cost-effective prices is also a common problem that MAH and cdmo will have to face. Only by expanding the batch and saving every cent of the cost, can it be possible to compete in the market to obtain the greatest competitive advantage, and it is also possible to survive and laugh to the end.
01 Entrustment agreement
Research agreement: when MAH cooperates with cdmo at the beginning, it is often the development of new products, so signing a commissioned research agreement is the first step. Mah is most critical only when it fully audits cdmo. Mah audit can either have an audit team familiar with R & D quality and production quality, or invite a third party to audit. The R & D quality system and data integrity of cdmo R & D laboratory are the two aspects that the audit focuses on most. The quality of R & D products should comply with the relevant requirements of ichq10, from drug development, technology transfer, commercial production, product delisting, clinical compliance with GCP and clinical trial drug management, followed by GMP. Quality management elements (PQS) include process performance and product quality monitoring system, correction and prevention system, change management system, management review, and quality booster is quality risk management and knowledge management. The research agreement mainly includes the scope of commissioned research, the rights and obligations of both parties, research progress milestones, acceptance criteria, and the corresponding R & D expenses paid. R & D progress and quality are not contradictory, and should complement each other. Progress without quality will lead to the disapproval of the project by the country, and the success and loss will collapse.
Production agreement: when the new product development reaches the process validation batch, the cooperation between MAH and cdmo has reached the commercialization stage. The commissioned production agreement mainly includes the name and specification of the commissioned product, the rights and obligations of both parties, the unit price of commissioned processing, etc. The most important consideration is whether the capacity of cdmo can meet the expected annual growth of MAH products after they are approved for listing. Both parties must have a deep discussion in this regard. Cdmo will also have its own ideas, which will ensure MAH has a basic annual output. The unit price of entrusted processing must be linked to the annual production, such as injection products, the production batch of 100000 and 10000 will not increase much in cost, Both parties will find an acceptable balance between production capacity and unit price. In addition to the process validation batch, the production agreement will also have preliminary pilot tests, engineering batches, etc., and there will be dynamic batch production to meet the registration and verification of the production site. At this time, both parties should consider whether to "combine the two in one" with the GMP compliance inspection. After all, according to the existing regulations, the dynamic inspection batch may be sold after risk assessment.
Quality agreement: the corresponding quality agreement will be signed whether it is commissioned research and development or commissioned production. The agreement will have version number management, and it can be revised and upgraded if necessary. The quality agreement will be required during the inspection of production license B and C, the drug registration and development site, the registration and production site, and the GMP compliance inspection. Just be careful not to have two versions of the agreement at the same time, but only the current effective version can be provided. The quality agreement can be drafted and revised with reference to the guidelines for quality agreement for commissioned production of drugs (2020 version) organized by the State Food and Drug Administration in September 2020, which is used to guide and supervise MAH and cdmo in fulfilling their drug quality assurance obligations. The quality agreement specifies in detail the various quality responsibilities of the holder and the trustee. MAH shall not entrust the obligations and responsibilities that can only be performed by MAH to cdmo through the quality agreement. Cdmo shall not re entrust production, but can re entrust inspection if there are no conditions. Focus of quality agreement: cdmo changes, deviations, how oos/oot is managed and who makes the final decision; Whether the entrusted finished product (preparation) inspection is entrusted to the production enterprise needs to have all the inspection conditions; Whether MAH must send personnel to the factory for supervision when commissioning production; Whether the ex factory release and marketing release processes of products are compliant and smooth.
02 Document management
Mah is a production license a or B, and the holder's quality management system should be established, first of all, the management document system of the enterprise should be established; The a certificate enterprise is a drug manufacturer, and the most important is the GMP system. It establishes a document structure similar to the six systems of FDA production, quality assurance, quality control, material storage, facilities and equipment, and packaging labels. In addition, the trustee entrusted by the holder with business communication and supervision also needs to add corresponding documents; However, certificate B has no drug production conditions and basically does not need to establish the GMP documents of the manufacturer, but the corresponding certificate B quality management documents need to be established article by article with reference to the inspection points for drug marketing license holders (Exposure Draft); If the B certificate is held by the R & D institution, the B certificate must also have its own R & D quality management system.
Cdmo includes entrusted R & D and entrusted production. Entrusted production corresponds to production license C (entrusted production), and entrusted R & D corresponds to cro business. The research and development of innovative drugs generally requires basic research, drug formation research, raw materials or stock solutions. After making preparations, CMC pharmaceutical research, pharmacological toxicology research, clinical research and approval for marketing are required. At each stage, corresponding quality management documents need to be established according to the scope of research, such as GLP system for animal experiments, GCP system for clinical trials, and GMP system from process validation to commercial production. Mah needs to be responsible for the whole life cycle management of drugs, the clinical and commercial marketing of drugs, and the establishment of clinical pharmacovigilance GVP and GVP for the treatment of post marketing adverse reactions and complaints.
The following is a list of documents on the research and development of pharmaceutical quality system and GMP document system
R & D pharmaceutical quality system: including R & D process management documents (SMP), which are used to standardize R & D project management; Operation management SMP, such as standardizing personnel, documents, QA, equipment, materials, QC, computer system, EHS and other business modules; SOP of operation technology is used to standardize the experimental operation. It also includes records and forms, such as standard accounts, experimental records and experimental reports. Finally, the registration template is used to standardize the writing of CTD declaration materials.
GMP document system (drug manufacturing enterprise): it can be divided into three levels. The top-level documents can include quality manual, factory owner document, pharmacovigilance manual, etc., the middle-level documents can include management standards, technical standards, work standards, and the bottom-level documents can be SOPs and corresponding records. Among them, a document of management documents (including records) is required, including document drafting, review, approval, reproduction, issuance, training, implementation, cancellation, revision, recycling, destruction, document storage, backup, borrowing and other activities, so as to ensure the traceability of documents.
02 Technology transfer
What is technology transfer?
In China's 2010 GMP guidelines (quality management system volume), drug technology transfer refers to the process of transferring the knowledge, technology and related products and processes of drugs from the R & D party or the holder to the receiver. In ICH Q10 quality management system, technology transfer refers to the transfer of knowledge obtained in the research and development and production of products and processes within and between production plants, which has achieved the purpose of product production. This knowledge lays the foundation for production process, control strategy, process validation method and continuous improvement.
Mah and cdmo can have several forms of technology transfer. First, MAH itself is a research and development institution, which is currently encouraged by the state and the most b-certificate form at this stage. If the new products are developed by their own R & D institutions, they need to transfer technology to cdmo manufacturers. Second, MAH itself has neither R & D nor production. Such enterprises are often established by sales individuals, or transformed from pharmaceutical trading enterprises and non pharmaceutical industries. The R & D of new products is entrusted to a cro, and the production is entrusted to cdmo. In this way, the technology of cro company needs to be transferred to the cdmo production plant. Third, MAH has neither R & D nor production, and the R & D and production of new products are all undertaken by cdmo enterprises. In this way, the technology transfer within cdmo needs to be carried out by R & D institutions and manufacturers. Fourth, MAH itself is a certificate, and there are also R & D institutions. A certificate can be developed by the R & D institutions internally, and then the internal technology is transferred to the internal production plant, and the technology of the internal production plant is transferred to the cdmo production plant. There should be other forms of technology transfer, which is no longer exhaustive.
Technology transfer generally includes the following transfer processes: first, MAH and cdmo sign a technology confidentiality agreement; Both parties set up a project team and formulate a project plan; Compare and evaluate the gap between the production conditions of both parties, and implement risk analysis and control; The transferor shall output the technical data (including technical process and analysis method), and the receiving party shall draft documents, records and schemes such as process procedures and quality standards, which shall be jointly reviewed and approved by both parties; Next, you can confirm the materials required for the transfer, including supplier audit, purchase, order placement, and final material arrival; Complete the transfer of analytical methods (including comparison, partial verification / confirmation, revalidation, exemption, etc.) before process transfer; Then enter the process "re" development, such as small-scale test, pilot test, large-scale batch, engineering batch, etc; Before the product process validation, it is necessary to confirm whether the plant facilities and equipment, sterilization, filtration, aseptic process (simulated filling, sealing, etc.), computerized system, etc. have passed the validation and meet the process validation conditions; Carry out risk assessment on collinear products, and carry out cleaning verification when necessary; The last important part is process validation, stability inspection, etc; Mah and cdmo jointly complete, review and approve all assessments and reports; Complete the technology transfer summary report and end the technology transfer project.
01 Normal operation of the system
After the successful technology transfer of MAH and cdmo, the new products can be subject to the registration verification of the National Bureau's development site and production site, or the "two in one" linkage Provincial Bureau can pass the GMP compliance inspection. MAH obtains the A or B production license, cdmo obtains the C production license, and both parties enter the daily production Commission operation. To ensure the normal and good operation of the quality management system of both parties, it is necessary to manage the changes, deviations, oos/oot and CAPA of both parties, and continuously improve and improve the quality management level of both parties.
Change management: MAH is the subject responsible for the change, and should comprehensively evaluate the impact of the change on the safety, effectiveness and quality controllability of drugs in accordance with the relevant provisions of the National Bureau. Both MAH and cdmo need to establish change control procedures. The risk level of changes related to entrusted products should be evaluated by MAH, and cdmo must be evaluated by MAH and reviewed in writing and approved by both parties before the change is implemented. If it needs to be filed with the Provincial Bureau or approved by the CDE of the National Bureau, MAH shall submit the application materials for the change study after fully changing the study in accordance with the relevant laws and regulations guidelines such as the technical guidelines for the change study of listed chemical drugs, traditional Chinese medicine and biological products