5 Must Know Things About Active Pharmaceutical Ingredients

Active pharmaceutical ingredients (APIs) are important compounds that are used in the manufacture of pharmaceutical drug products. APIs are biologically active and intended for the treatment of diseases. The quality of the API plays a vital role in the quality of a drug product. Quality should be built in by design.


Regulatory compliance is the first and last step to follow by the API manufacturers. Rules and regulations are very clearly defined in every country. Quality is not a choice, it's a mandate. Latest technology bringing enormous changes in the manufacturing techniques and transparency in every aspect. The pharmaceutical industry is not an exception to this. It has to adopt the upcoming technologies to bring more transparency in its activities. Recent regulatory audits revealed many malpractices, followed by some companies, in making of medicinal products.

In this context, let us try to understand the important aspects of active pharmaceutical ingredients. There are so many things to focus on, but, today we will discuss only 5 essential things which can cover a broad range of manufacturing requirements. They are:

  1. 5 Essential Things To Know About APIs
  2. 1. Manufacturing Facility of the Active Pharmaceutical Ingredients (API)
  3. 2. Relation Between Raw Material's Quality and Active Pharmaceutical Ingredient's Quality
  4. 3. Control of the Impurities in Active Pharmaceutical Ingredients (API)
  5. 4. Handling and Storage of the Active Pharmaceutical Ingredients (API)
  6. 5. Importance of Compliance Management System in API Manufacturing

Let us discuss in detail one by one.

1. Manufacturing Facility Of The Active Pharmaceutical Ingredients (API)


Medicines are intended for human use. They can cure the diseases, but, equally, they can do harm also if the quality of medicine is compromised. Quality of medicine starts right from the starting material. Exceptions are not allowed at any stage of manufacturing whether it is in formulations or bulk drug industry.

The bulk drug industry is more critical than formulations since it is manufacturing active pharmaceutical ingredients which are biologically active. The fundamental differences between these two industries are plant configuration and processes or technologies.

Plant design is the base for the quality of active pharmaceutical ingredients (APIs). Plant design includes everything inside the plant premises. It includes reactors, waste disposal system, storage of materials etc.

Safety measurement plays a crucial role in the manufacturing process of APIs. Many synthetic routes contain inherent hazardous chemical reactions. A Compromise in safety-related decisions definitely leads to fatal incidents and huge property loss. Safety means it is not only related to humans and physical property, but also to the environment. It is the responsibility of the manufacturers to keep the environment safe from chemical pollution.

The plant should be constructed in a contamination free environment. The dust in the air may contaminate the products if proper care is not taken. For example, an API plant near a cement factory is not advisable. If the situation is unavoidable and your process includes open tanks, then you must include a filtration step before crystallization of the product. Strict measures are needed to protect the product from insects too.

The next important thing is hygiene and sanitation. Good hygiene practice leads to a good sanitation culture. Employees working in the industry must understand the significance of hygiene and sanitation. Management should provide meaningful training to their employees on the subject.

Hygiene and sanitation are not limited to a single area. It applies to the entire plant, including personnel. Floors, walls and ceilings cleaning with contamination-free liquids or solvents, regular cleaning of remote areas, the closing of breeding areas, sanitization of clothes and removal of stagnant water are some to illustrate. Toilets and canteen should be far away from production blocks.

Personnel hygiene is also an important factor to keep the drug safe from contamination. A simple habit of proper cleaning of hands prevents contamination. Prohibit drinking alcohol and smoking in plant premises. Personnel suffering from an infectious disease should not be allowed into production activities.

Unsatisfactory final facilities may lead to regulatory impositions and the closing of the factory. Recently, many companies got US FDA warning letters for the poor maintenance of manufacturing plants.

2. Relation Between Raw Material's Quality And Active Pharmaceutical Ingredient's Quality


The quality of the raw materials is the foundation of API's quality. Best procedures must be in place to ensure the quality of Raw materials without distinction of domestic or imported.

The discerning factors of raw material's quality are physical and chemical properties and purity of the compound. Companies have to conduct regular audits in the sites of their raw material suppliers to ensure the quality. Companies should declare a quality-based selection process of raw material vendors.

Established quality systems, plant design that complies with regulatory requirements, employees with the required qualifications, a well equipped analytical laboratory and a strong R&D support to the production department should be the criteria for raw material vendor selection.

The poor quality of the raw materials ultimately leads to the poor quality of active pharmaceutical ingredient. An API with a poor quality is unsafe and you can not use it for the treatment purposes. Analytical methods have limitations in identifying the impurities. If any impurity skips due the limitation of laboratory testing method, it will lead to a major disaster. Example:Heparin disaster in 2008.

81 deaths happened in this fatal incident. Heparin is a blood thinner and used in surgeries and dialysis. Baxter, a pharmaceutical company, imported the API, Heparin, from China to make finished dosages. Baxter manufactured Heparin injections and solutions and released them into the USA market. The released medications showed adverse reactions such as serious allergy and low blood pressure in the patients. US FDA identified 350 adverse events and 81 deaths that happened with the use of Baxter Heparin. During the investigation, US FDA found that the Heparin was contaminated with over-sulfated chondroitin sulfate.

Actually, Heparin is a natural product. It exists in pig's blood vessels. The collected crude Heparin from pigs is further refined and made into an API. Due to the shortage of the required type of pigs and cost impact, Chinese manufacturers of Heparin, chosen an alternative root to meet the business requirements.

Chondroitin sulfate is also a natural product and it can be made from animal cartilage. It is cheaper than crude Heparin. But with a certain chemical modification of it, over-sulfated chondroitin sulfate can be produced. This mimics real Heparin and also cheaper than it. Now you can easily understand what had happened in this case.

Chinese manufacturer of Heparin, who supplied it to Baxter, adulterated the Heparin API with over-sulfated chondroitin sulfate. This over-sulfated chondroitin sulfate was not identified in the routine laboratory testing method because it mimics Heparin. Later on, FDA inspected the Chinese company and found many lapses in the manufacturing process. A warning letter was issued to the company. Hence, API manufacturers should be cautious about their raw material's quality.

Pls refer the below document for more details:

From the U.S. Government Printing Office

Some raw materials cannot be tested due to their hazardous nature and difficult to handle in the QC laboratory under normal conditions. In such cases, API manufactures usually accepts the materials based on the certificate of analysis. Examples are bromine, dimethyl sulfate and phosphorous pentachloride. In such cases, API manufactures should conduct thorough vendor audits and ensure the quality periodically.

3. Control Of The Impurities In Active Pharmaceutical Ingredients (API)


Already we have seen, in the above section, the effect of impurities on patients. Identification and control of impurities are the primary responsibility of API manufactures. During the synthesis of API, many unwanted chemicals may produce and stay along with the final product. The chemicals other than the API are called impurities. Impurities may form in other ways also. Impurities have no clinical value and additionally, they will harm the patient.The severity of side effects depends on the nature and category of impurity.

No chemical synthesis can produce 100% desired product. Always impurities accompany the product. This is the fact. Impurities are three types: 1. Organic impurities (process and drug-related) 2. Inorganic impurities 3. Residual solvents. These impurities enter into the main product's impurity profile during the manufacturing process.

Many practical problems may arise during the manufacturing process. Sometimes, due to mechanical problems in the plant, the reaction may prolong for hours than the actual lead time. Then obviously impurities will form. Maintenance of machinery in good condition is one of the necessary requirements to control the generation of impurities.

Chemicals have a natural tendency to react with other materials when they receive sufficient energy. The source of energy may be in the form of heat or light. Storage of raw materials and the API is a very critical factor in controlling the impurities. When products are exposed to light, impurities would rise due to photochemical degradation. Excessive heat leads to internal reactions and chemical changes, which in turn, creates a path to impurities by thermal degradation.

Impurities associated with raw materials can find their way into the API and contribute in its impurity profile. They can escape from the purification process for the reason that they are close enough in properties with the main compound. Adequate analytical methods, which can detect these impurities, must be in place at each processing step. This exercise is not limited to raw materials, it applies to by-products, intermediates, reagents, ligands, and catalysts also which have a probability to appear in the API impurity profile.

Solvents are used as vehicles in the organic synthesis. Their use in the preparation of solutions or suspensions is inevitable. Chances are high, to appear the residues of these solvents, in the impurity profile of the API. Guidelines are already available which made by the authorities defining the allowable limits of these residual solvents in the active pharmaceutical ingredient's impurity profile.

Impurities can be identified or unidentified. There should be a clear documentation on the possible impurities and their control strategy. Any impurity, which is present in greater than the identification threshold, in any batch, should be identified. Analytical procedures must be developed and validated to identify all potential impurities. Special care and attention are needed to control the genotoxic impurities. These impurities must be tested with appropriate validated methods.

Regulatory authorities allow your products into their regions only when you have precisely identified and controlled all the potential impurities. No government wants to put their people's health at risk.

4. Handling And Storage Of The Active Pharmaceutical Ingredients (API)


There should be defined individual areas for the storage of raw materials and APIs. Cleaning, maintenance, and appropriate arrangements that can prevent objectionable microbiological contaminants are the main factors to consider for the storage of these compounds. Containers that are used to store APIs should contain the best quality and must be capable enough to withstand against deterioration. Use cleaned and sanitized containers only for the storage of intermediates and APIs.

Handling of raw materials and APIs should be done in accordance with the well-written procedures. Records must be available for the receipt and distribution of raw materials and APIs. All raw materials shall be kept in a quarantine area until the testing is completed. If the material is not meeting with the predefined specification, move it to the rejected area which has access to the authorized persons only. Appropriate procedures should be in place for the identification and sampling of all raw materials.

APIs should be stored under appropriate conditions that are determined based on stability studies. Temperature and humidity control systems must be arranged in the drug storage areas.

All APIs should have records with clear details such as when they received, how much quantity, batch number, to whom it was distributed with what quantity, and expiry date.

APIs that are packed in fiber drums shall not be placed directly on the floor. They must be kept on the pallets with sufficient space that allows cleaning and inspection.

Rejected APIs must be clearly identified and moved to the appropriate area where the authorized persons only can have the access. The same procedure applies to recalled APIs also.

Packing and repacking of active pharmaceutical ingredients shall be done according to the cGMP requirements.

Repacking is a common activity in the industry. This happens especially with brokers.

Brokers take the bulk quantities and repack it into smaller quantities based on the orders they received. So the design of the packing facility must avoid mix-ups and cross-contamination. A perfect care is needed to identify and label the materials.

All packaging materials used for the storage of raw materials and active pharmaceutical ingredients must be tested for their quality and ensured for their inertness to react with products.

The packaging material should not allow the moisture, light, and oxygen from the atmosphere. It must have the capacity to protect the material from biological contamination. All these properties of packaging materials should stay throughout the shelf-life of the product.

The bad packaging of APIs leads to so many serious consequences such as product deterioration and recall. It creates doubts on the system of quality assurance in the company. Regulatory agencies may consider this issue as a serious one and may review the whole quality system of the firm.

Product recalling procedures should be in place to handle the product, in case any quality issue arises after the drug distribution to a customer.

The above discussion makes it clear that the product's quality unequivocally depends upon the storage and handling methods and processes.

5. Importance Of Compliance Management System In API Manufacturing


"Compliance" refers to a system, which firms have to follow, to produce a product with high quality. Compliance ensures the quality of a product. cGMP is one of such systems to comply with. Compliance with current good manufacturing practices (cGMP) dictates the future of API manufacturers and it is the backbone of the API industry. GMP is an inherent responsibility of API manufacturers.

Medicines are for human use. Good quality of medicines helps the patients recover from their illness safely without the confrontation of any major side effects. Protection of public health is the primary responsibility of governments in any country. Accordingly, governments bring so many laws into effect to protect their people's health.

cGMP is also one of the statutory and regulatory requirements. Hence, implementation of good manufacturing practices in the pharmaceutical industry is mandatory and a legal requirement.

All activities of the manufacturing process shall be performed by well trained and qualified persons. Everyone in the company is responsible for the Quality; right from contract labor to CEO.

The term "manufacturing" in "Good Manufacturing Practices" has a broad meaning. It covers many operations in the drug-making process. The main activities come under the scope of the word "manufacturing" are: receipt of raw materials, packaging and repackaging, labeling and relabeling, production, product storage, product release, product distribution, quality control activities, online documentation, investigation of failures, hygiene and sanitation and many other things related to manufacturing process.

GMP applies from the starting point of the process to drug distribution into the market.

Compliance with cGMP ensures drug safety, quality, and purity. Well designed in-process checks, qualified suitable equipment, the establishment of the specification for raw materials, intermediates and in-process controls, validated analytical methods, an annual review of the API quality, stability testing, and investigation of out of specification (OOS) materials, all these are the regulatory requirements.

Failure to meet these requirements leads to the warning letters from regulatory agencies and the halt of the exports. If you observe recent warning letters issued by the US FDA, one thing comes to our notice that many issues are related to laboratory controls, quality system, equipment, records and reports, inadequate investigation of failures, inadequate procedures and data integrity.

Regulatory inspectors witnessed so many malpractices across the globe in the pharmaceutical industry. Especially data integrity has become a serious issue with the industry.

Regulations are subject to change over time depending on the current needs. The industry has to respond dynamically according to the changing needs and meet the latest requirements.

Warning letters and import alerts reduce the brand value of a company which has been earned by many years of hard work. There are no shortcuts to bring the quality in a product.

Pls refer the below document for more details on cGMP:

Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
Guidance for Industry


Increasing regulatory audits and the change in the nature of the audit, exposing the prevailed malpractices in the industry from time to time. At present, the pharmaceutical industry is facing hard times. Increased quality costs affecting their revenues. Anyhow, it's mandatory to meet the regulatory requirements.

The design of the facility has a lot of importance in the regulatory point of view. So many requirements are set forth to make active pharmaceutical ingredients with the best quality.

Manufacturers should be careful of incoming raw material's quality and always to ensure it by conducting periodical quality audits at the supplier's site.

Impurities associated with raw materials can contribute to the impurity profile of an API. Materials should be stored under controlled conditions to prevent chemical degradations. Separate storage areas should be available for raw materials and APIs.

Records should be maintained for the receipt and distribution of raw materials and active pharmaceutical ingredients. Packing and repacking shall be done according to cGMP requirements.

Ensure the safety, quality, and purity by following good manufacturing procedures. Failure to meet cGMP requirements may lead to the warning letters which shall impact the overall business of the firm.

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Author Profile


Ram Kumar Reddy

Ram Kumar Reddy is the founder of Pharma Times Now. Helping students of Pharmacy and Chemistry and employees in the pharma industry in learning pharmaceutical science. Ram Kumar Reddy has 24 years rich experience in the Pharmaceutical industry and well versed in quality systems. He worked with Dr.Reddys and Sai Life Sciences. He lives in Hyderabad, India.

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