HOME  ⁄  NEWS  ⁄  Overview of High Pot...

Overview of High Potency Pharmaceutical Production

time:2020-02-19

In recent years, there is a specific category of drugs with the fastest growth rate in the complex API, that is, High Potency Active Pharmaceutical Ingredients (HP API). It is a kind of drug composition with high pharmacological activity. Because of the lower clinical dosage and fewer side effects of HP API, it has attracted market attention and become one of the research and development hotspots in recent years. 


For High Potency Pharmaceutical, Different Institutions have Different Definitions or Standards


The GMP guidelines for CH Q7 APIs indicate:


• high pharmacological activity or toxicity …(e.g., certain steroids or cytotoxic anti-cancer agents).


• highly sensitizing materials, such as penicillins or cephalosporins.


ISPE Guide - Risk based pharmaceutical production provides standards for high potency pharmaceutical: 


According to the standard of identifying dangerous drugs and ranking according to risk assessment 


•Genotoxic compounds are known or highly likely to cause cancer


•Compounds that can affect the reproduction and / or development may be caused at low doses.


•Severe target organ toxicity, anaphylactic shock, or compounds of other major adverse reactions may be caused at low doses.





Implementation of risk-based prevention of cross contamination in EMA products and how to use risk identification to establish health exposure limit guidelines when multiple products are in common line


Q & A: what products / active substances are considered at high risk?


(1) Known genotoxic (especially mutagenic) compounds or most likely human carcinogen. This group of compounds is easy to identify because genotoxicity is related to pharmacology, such as DNA alkylation cell inhibitors, and its application is usually limited to the use of their respective warning statements as tumor markers in product characterization summaries.


(2)Compounds that can affect the reproduction and / or development may be caused at low doses. For Example, there is evidence that this effect can be caused when the clinical dose is less than 10 mg / day (the animal dose is equivalent to 0.02 mg / kg) or the dose in animal studies is less than 1 mg / kg / day.


(3)Severe target organ toxicity, anaphylactic shock, or compounds of other major adverse reactions may be caused at low doses. For Example, there is evidence that this effect can be caused when the clinical dose is less than 10 mg / day (the animal dose is equivalent to 0.02 mg / kg) or the dose in animal studies is less than 1 mg / kg / day. 


(4)Substances with high pharmacological effect, recommended daily dose is less than 1 mg (animal dose is equivalent to 0.02 mg / kg).


(5)Substances with high potential for sensitization


Types of high potency pharmaceutical 


Classification of antineoplastic agents




●Cytotoxic drugs are highly toxic.


●Although hormone drugs are not highly toxic, they belong to high potency pharmaceutical.


●Auxiliary drugs include narcotic drugs


Toxicity classification of highly toxic drugs



Application prospect of high potency pharmaceutical 


High potency pharmaceutical have a wide range of therapeutic fields. Many pharmaceutical products contain HP APIs, which are scientifically proved to be able to play a therapeutic effect at a smaller dose level than traditional APIs. The most typical characteristic is Antibody–Drug Conjugates (ADC).   


ADC is a new type of cancer treatment method with good application prospect. It is a combination of monoclonal antibody targeting specific antigen and high-efficiency cytotoxic small molecule chemicals. It selectively delivers high-efficiency cytotoxic small molecule chemicals to specific tumor cells through monoclonal antibody. This specific treatment method of attacking cancer cells makes non cancer cells free from cancer Toxic injury.


On February 10, 2020, Kerui Wei'an released the annual report of "2020 most noteworthy drug forecast", which predicted that 11 new drugs will be launched in 2020 and the sales volume is expected to exceed 1 billion US dollars in 2024. Among these 11 drugs, there are two antineoplastic drugs. Coincidentally, these two drugs are all antibody drug conjugates (ADC).


Since the first ADC drug came into the market in 2000, ADC has been tepid in the industry. Until 2019, FDA approved three ADCs (Polivy、Padcev and Enhertu), which ushered in its outbreak period. All of these confirmed the feasibility of this kind of "armed" antibody in the treatment of cancer. At the same time, the field of antibody coupled drugs has also attracted more attention from the outside world. All of these confirmed the feasibility of this kind of "armed" antibody in the treatment of cancer. At the same time, the field of antibody coupled drugs has also attracted more attention from the outside world.



According to the reports of markets and markets, the global market size of high activity APIs in 2016 is US $14.4 billion, which is expected to grow at a compound annual growth rate of 10.3% in the future and expand to US $33.87 billion in 2025.


Although the market of highly active drugs is broad, they also face great challenges. In order to produce high activity drugs, we must have advanced hardware equipment, scientific experimental design, advanced sealing technology and highly trained and skilled operators, so that we can safely produce them.


Requirements of legal guidelines  


3.6 …Dedicated facilities are required for manufacturing when a medicinal productpresents a risk because:

ii. scientific data from the toxicological evaluation does not support a controllable risk (e.g. allergenic potential from highly sensitising materials such as beta lactams)or


3.24 Highly active materials or products should be stored in safe and secure areas.


Chinese GMP


Article 28 Personnel working in high-risk operation areas (such as production areas of high activity, high toxicity, infectivity and high sensitivity materials) shall receive special training. 


Article 46 In order to reduce the risk of pollution and cross pollution, the plant, production facilities and equipment shall be reasonably designed, arranged and used in accordance with the characteristics, technological process and corresponding cleanliness level of the drugs produced, and shall meet the following requirements:


The feasibility of multi product sharing of factory buildings, production facilities and equipment shall be determined by comprehensively considering factors such as characteristics, process and intended use of drugs, and corresponding evaluation reports shall be provided;


Special and independent workshops, production facilities and equipment must be used for the production of drugs with special properties, such as highly sensitized drugs (such as penicillin) or biological products (such as BCG vaccine or other drugs prepared by active microorganisms). The operation area with large dust production of penicillin drugs shall be kept under relative negative pressure, the exhaust gas discharged to the outdoor shall be purified and meet the requirements, and the air outlet shall be far away from the air inlet of other air purification systems;


Special facilities (such as independent air purification system) and equipment must be used for the production of β - lactam structural drugs and sex hormone contraceptives, and they must be strictly separated from other drug production areas;


Special facilities (such as independent air purification system) and equipment shall be used for the production of certain hormone, cytotoxic and highly active chemicals; in special circumstances, if special protective measures are taken and necessary verification is conducted, the above pharmaceutical preparations can share the same production facilities and equipment through staged production;





One-time production equipment emerges as the times require


Because the production requirements of HP APIs are strict, and the investment cost is high, some pharmaceutical companies choose to entrust the business to the powerful outsourcing organizations such as CMO/CDMO, to develop high activity drugs by using small molecule APIs and biological APIs, and to realize commercial production.


The equipment in the workshop of pharmaceutical enterprises and CMO enterprises will develop one or more highly active drugs at the same time in a certain period of time. Therefore, special protective measures and necessary verification (equipment cleaning verification) are required before the same set of production facilities and equipment can be shared through staged production mode, or one-time production equipment can be directly selected to avoid the cleaning verification of equipment.


 One-time preparative liquid system from Hanbon


Avoid cleaning verification reasonably with one- time preparative liquid system


Hanbon Science and Technology Co., Ltd. organized technicians to assist our customers in developing one-time preparative liquid system to meet customers’ purification needs of HP API production. Now, Hanbon has established cooperation relationship with well-known CDMO enterprises in China. Hanbon has haven a clear understanding of customers' needs, and can develop effective technical solutions for them. 


In the one-time preparative liquid system, the parts contacting the liquid can be replaced (such as pump head, pipeline, flow cell, mixer, sample valve, loop, online filter, etc.), so as to ensure that there is no cross contamination between drugs, using safety, avoiding CIP / SIP, and reducing the cleaning verification link. It can save time cost and manpower cost of cleaning verification for users.