Ingredients

Quality and price of active ingredients and their impact on effectiveness and potency of medicine

Dr Md Anawar Hossain

• The good quality of active pharmaceutical ingredients (APIs) can ensure the manufacturing of the high quality, effective and safe essential drugs, while the use of low quality APIs can produce less effective and unsafe drugs.
• The price volatility of APIs can affect the small pharmaceutical companies.
• One potential way to address the above problems would be to broaden the WHO prequalification system and include APIs for drugs that are on the WHO model list for essential medicines.

Prequalification of Active Pharmaceutical Ingredients

Prequalification of active pharmaceutical ingredients (APIs) is an important step to ensure the production of good quality APIs. These products should be manufactured in compliance with WHO (World Health Organization) Good Manufacturing Practices (GMP). The pharmaceutical companies should use the prequalified APIs to manufacture their finished pharmaceutical product (FPP).  

     The API manufacturers must submit their API master file procedure (APIMF) to get their application approved for prequalification of an FPP (WHO, 2022). The APIMF includes the manufacturing details, quality controls procedure, accepted active ingredient specifications, and the assay and related substances test methods for assessment and any changes, before or after prequalification, is included in the updated APIMF version, which, therefore, clearly identify an API with a specific APIMF version. Active pharmaceutical ingredient manufacturers should apply to receive a WHO Confirmation of API Prequalification and obtain successful prequalification, before their APIs are included in the WHO List of Prequalified Active Pharmaceutical Ingredients (WHO, 2022).

API Manufacturer’s Site Inspection

The site of the API manufacturer should be inspected by WHO and verified whether it complies with WHO GMP requirements (WHO, 2022). The API manufacturing companies should apply along with a site master file (SMF) for each manufacturing site of each API and intermediate involved in the preparation of the API related to prequalification sought. An SMF contains the information about the production and/or quality control of pharmaceutical manufacturing operations conducted at a site, and any related integrated operations conducted at adjacent site or buildings.

Source, Quality and Price of Active Pharmaceutical Ingredients

The good quality of active pharmaceutical ingredients can ensure the manufacturing of the high quality, effective and safe essential drugs. The manufacturing cost of the final finished medicine product depends on the purchase price or manufacturing cost of APIs. In the developing countries, most of the pharmaceutical companies purchase APIs from other manufacturers. Only a limited number of large manufacturers of finished pharmaceutical products have their own API manufacturing capabilities in the developed countries, but none of them can make all required APIs in-house. The small manufacturers in developing countries face difficulties to source the global API market and ensure that they get a quality product at a fair price. Besides these, there is possibility that the greedy manufacturers or traders can control or monopolize parts of the API market for essential medicines with low commercial attractiveness. Given the limited sources of APIs, the manufacturers can increase the price of APIs to make more profit (Bumpas and Betsch, 2009).

One potential way to address this problem would be to broaden the WHO prequalification system and include APIs for drugs that are on the WHO model list for essential medicines.

Quality of APIs and Their Effect on Effectiveness of Medicine

The high quality of active pharmaceutical ingredients has a great effect on the effectiveness and safety of medicines. Active pharmaceutical ingredient is the central component of medicine. Sometimes, more than one API is used in one medicine. The quality requirements of an API help the manufacturer to determine the use of ingredients and the permissible limit of usage.

Properties and Purity of APIs

The active pharmaceutical ingredient has three main properties such as physical, chemical and biological properties, which can be used in the treatment of diseases. Active pharmaceutical ingredients may have chemical impurities. In addition, the impurities may come from the solvent used in mixing of ingredients. Therefore, the manufacturers should test the potency of the medicines. The physical properties of APIs, such as particle size/proportion and polymorphism are critical factors for suitability of an API for drug use, which control the flow properties of the API, rate of absorption and the bioavailability of the medicine. The particle size of the ingredient controls the solubility of the medicine in human body. The manufacturing process must ensure that the APIs are clean enough for use in non-sterile dosage formula, free from biological threat and toxins (Mankind Pharma, 2022).

References

Bumpas J, Betsch E, 2009. Exploratory study on active pharmaceutical ingredient manufacturing for essential medicines. Health, Nutrition and Population (HNP) discussion paper; World Bank, Washington, DC. © World Bank. https://openknowledge.worldbank.org/handle/10986/13682 License: CC BY 3.0 IGO.

Mankind Pharma, 2022. Quality factors for active pharmaceutical ingredients. Link: https://www.mankindpharma.com/blog/quality-factors-for-active-pharmaceutical-ingredients. Accessed on 13/06/2022.

WHO, 2022. Active Pharmaceutical Ingredients. Prequalification Procedures and Fees: FPPs, APIs & QCLs.

Quality, ratio and adverse reactions of inactive ingredients/excipients in medicine

Dr Md Anawar Hossain

Excipients and their uses in medicines

All other materials except active pharmaceutical ingredient in medicines are called pharmaceutical excipients or inactive ingredients (Haywood and Glass, 2011). Excipients are considered as inactive ingredients or inert materials, however, studies over the past years indicated the adverse reactions from them. Appropriate drug delivery system plays a significant role in treatment of diseases. Nowadays, drugs are delivered in many dosage forms including tablets, capsules, oral liquids, topical creams and gels, transdermal patches, injectable products, implants, eye products, nasal products, inhalers and suppositories. The excipients play a significant role in drug delivery system via different ways as below:

1. The excipients or inactive ingredients are mixed with active ingredients to increase the physical properties (size and form of tablets, capsules and other solid forms of medicines),

2. To aid the manufacturing process and formulation development,

3. To protect, support or enhance stability, solubility, permeation, absorption (Ullmann, 2022), or bioavailability or patient acceptability and compatibility (Haywood and Glass, 2011).

4. Therefore, they are considered not just as inert ingredients in a formulation, but as functional ingredients facilitating the therapeutic function of the active ingredients.

5. The excipient controls the drug release so that it does not release too early in the assimilation process in places where it could damage tender tissue and create gastric irritation or stomach upset (Dave, 2008).

6. Some excipients help the drug to disintegrate into small particles accelerating their flow into blood stream, while other excipients protect the product’s stability giving it maximum effectiveness at time of use (Dave, 2008).

7. Some excipients are used to aid the identification of a drug product.

8. Some excipients are used to make the product taste and look better, especially for children.

9. Excipients are also used as diluents or fillers, binders, disintegrants, lubricants, colouring agents and preservatives, which are essential components of drug manufacturing process.

Ratio of pharmaceutical excipients and active ingredients

Pharmaceutical excipients are very essential components of a modern drug manufacturing process, although they are considered to be pharmacologically inactive. Their quantity makes up the bulk of the total dosage form in many products (Dave, 2008). Thousands of different excipients are used in manufacturing medicines and, on average, each product contains about 90% excipients (Haywood and Glass, 2011). Reker et al. (2019) characterized the abundance and complexity of inactive ingredients in approved medications. They reported that a majority of medications contain inactive and active ingredients that could cause adverse reactions. Therefore, it is very essential to enhance the safety of medications and their inactive ingredients. We should have pre-analysis of the ingredients contained in medications whether they have any possibility of reactions resulting in harmful by-products and new products.

Patient specific formulation of medications

The amount or ratio of inactive ingredients and active ingredients in pills or capsule should be clearly reported, so that the patients and health care providers can understand the ingredients what they are ingesting in. Some of the patients might be allergic or intolerant to some ingredients. Some excipients might have the potential to alter the pharmacokinetic properties of an active pharmaceutical ingredient by different reactions, such as physicochemical interactions or by modulating metabolic and transport enzymes (Reker et al., 2019). Developing a specific formulation of medications considering a specific sub-population of patients could thereby not only avoid adverse reactions but help to achieve fine-tuned pharmacokinetic and metabolic profiles.

Possible adverse reactions by excipients

The excipients used in medicines should be pharmacologically inactive, non-toxic, and non-reactive with the active ingredients or other excipients. Actually, few excipients fulfil the above ideal characteristics. Some excipients are proved to be not inert, and they have ability to react with other ingredients in the formulation. They also cause adverse and hypersensitivity reactions in patients which can be a mild rash to a potentially life-threatening reaction (Haywood and Glass, 2011). The excipients, either solid powder or solvents, used in the manufacturing of medicines or their by-products/residues may cause multiple toxicities (Haywood and Glass, 2011). Different pharmaceutical manufacturers use different excipients, especially preservatives and colourants to produce the same drug. The Consumer Medicines Information provides a list of excipients, and information on the safety of individual excipients can be found in drug reference guides.

     Some patients face an adverse reaction after ingestion of medicines, and they are not sure how they are encountering adverse reactions. The adverse reactions may occur not always from the active ingredient, but also it may result from the similar ingredients if the patient is sensitive to those, or if the patient is taking multiple medicines. The adverse reaction may occur if the quantity of excipients may be high relative to body weight, especially for premature babies. The adverse reaction might result from the excipients contained in their current and past medication history too. Therefore, the patient should identify which factors are causing their individual adverse effects.

     Diluents or fillers can significantly affect the physico-chemical properties of the final tablet thus affecting the biopharmaceutical profile. As for example, calcium salts, used as fillers, can interfere with the absorption of tetracycline from the gastrointestinal tract indicating that excipients may not always be inactive or inert material in a drug (Dave, 2008). Therefore, the pharmaceutical manufacturers should carefully select the diluents, binders, lubricants and glidants to avoid the adverse reactions, but maintain the product stability and disintegration capacity for drug release after ingestion.

Use of excipient in preparation of tablet

The international pharmacopoeias contain the list of excipients, and their uses. The same excipient has multiple uses. The manufacturing of tablets can be a complex process. Therefore, the formulation expertise should focus on precaution to produce a product that will be stable during storage, transport and handling. The tablet should be dissolved homogenously and release its active pharmaceutical ingredient as required once ingested.

Dangers to children from excipients use in medicines

Some studies reported that, in some formulations for children, excipients are often used at higher concentrations than the recommended levels in international paediatric guidelines, while inappropriate labelling enhances the potential risks associated with the various excipients (Rouaz et al., 2021). The paediatric safety profiles related to the age and development of excipients often are different from those of adults.

     Some toxic excipients are used in formulations for the neonates/newborn children, which include sodium benzoate, propylene glycol, methyl para hydroxybenzoate, propyl, sodium saccharine, benzyl alcohol, benzalkonium chloride, polysorbate 80 and ethanol. European new-borns receive several potentially harmful pharmaceutical excipients: parabens, polysorbate 80, propylene glycol, benzoates, sodium saccharine, sorbitol, ethanol and benzalkonium chloride.

     Detailed information about the used excipients is missing in paediatrics. Therefore, it is very essential to conduct new research and develop new guidelines about the use of excipients in medicines for children, which can increase the safety and reduce toxicity of excipients from the adverse effects in paediatric populations. Gallon formulators can formulate safer, more stable and higher quality products.

     The pharmaceutical manufacturers should consider the possible adverse effects of the active ingredients and the excipients used in the paediatric population because the excipients that are safe for adults, may not be safe for children.

References

Dave R.H., 2008. Overview of pharmaceutical excipients used in tablets and capsules. Drug Topics Journal, October 24, 2008. Link: https://www.drugtopics.com/view/overview-pharmaceutical-excipients-used-tablets-and-capsules. Accessed on 20/05/2022.

Haywood A., Glass BD., 2011. Pharmaceutical excipients – where do we begin? Aust Prescr 34, 112-114. https://doi.org/10.18773/austprescr.2011.06

Reker D, Blum SM, Steiger C, et al. 2019. “Inactive” ingredients in oral medications. Sci Transl Med. 11(483): eaau6753. doi:10.1126/scitranslmed.aau6753.

Rouaz K., Chiclana-Rodríguez B., Nardi-Ricart A., Suñé-Pou M., Mercadé-Frutos D., Suñé-Negre J.M., Pérez-Lozano P., García-Montoya E., 2021. Excipients in the Paediatric Population: A Review. Pharmaceutics 2021, 13, 387. https://doi.org/10.3390/pharmaceutics13030387.

Ullmann P, 2022. Excipient selection for compounded pharmaceutical capsules: they’re only fillers, right? EDUCATION PRACTICE UPDATE. Link: https://www.medisca.net/pdf/published-articles. Accessed on 20/05/2022.

Biologically Active Excipients Need Clinical Investigation

Dr Md Anawar Hossain

What are excipients used in medicine?

Pharmaceutical formulation of a drug product consists of the active pharmaceutical ingredient (API) and excipients. The excipients are called inactive ingredients. According to the U.S. Food and Drug Administration (FDA), the excipients are “any component of a drug product other than an active ingredient”. Most of the drugs (pill, liquid or injectable) contain a relatively small amount of their active pharmaceutical ingredient by mass, while the rest of composition includes inert ingredients or excipients, such as preservatives, dyes, antimicrobials and other compounds. These supposedly inert ingredient may potentially be biologically active causing unanticipated side effects, according to a preliminary new study by researchers from the UC San Francisco School of Pharmacy and the Novartis Institutes for BioMedical Research (NIBR). Their new study was published online in Science, July 23, 2020 (Weiler, 2020). 

• They systematically screened 3,296 excipients contained in the inactive ingredient database, and identified 38 excipient molecules that interact with 134 important human enzymes and receptors.
• Their study did not look for actual effects on human patients,
• They only intended to flag molecules with the potential to pose negative health effects,
• It needs to be further studied to understand how they might contribute to side effects of drugs in which they are found.

Why are excipients used in medicine?

Excipients are used in medicine to increase

• product shelf stability and preservation,  
• maintaining tonicity,
• facilitating drug delivery,
• ensuring the development of the most efficacious medicine,
• avoiding immunogenic or other side effects,
• Delivering medicine safely and effectively,
• Distinguishing pills by color.

Problems in use of excipients

The use of these additive materials may have potential implications for clinical consideration. The safety risk of excipients should be assessed considering their type and variability (Ionova and Wilson, 2020).

• Excipient termed as inactive” ingredients are not as inert as the name suggests.
• Excipient complexity has been identified in 230 biological formulations,
• Excipient-related adverse effects have been identified,
• Most commonly occurring excipients are water, sodium chloride, polysorbate 80, sucrose, and mannitol,
• Many formulations don’t demonstrate the concentration of the most commonly occurring inactive ingredients,
• Literature survey reported some case reports of excipient-related adverse events,
• These cases included injection site reactions, anaphylaxis, hyperglycemia, and acute renal failure,
• The use of appropriate excipient in medicine is significant because about 92.8% of oral medicines contain at least one potential allergen in its formulation,
• Inactive ingredients in parenterally administered medicines have been associated with increased sensation of pain at the injection site,
• Some inactive ingredients have been identified as the potential factors impacting immunogenicity of biologics,
• These ingredients can exert adverse effects on sensitive and intolerant people, particularly on vulnerable pediatric and elderly people, who have serious and life-threatening diseases and they need treatment with unstable biological medicines.

Biologic drug product

The formulation development of biological drug products has some difficulties due to their complexity and fragility (Ionova and Wilson, 2020).

• First, stability and preservation present a significant challenge as the API of a biologic is more unstable than in small molecule drugs.
• Protein-based therapeutics have a potential to cause an immunogenic response leading to adverse events that are often not discovered until after the medicine is on the market.
• Most of these medicines must be developed in a liquid form for compatibility with subcutaneous, intramuscular, or intravenous administration.

Present and future of biologics

• The biologics are the fastest growing drug products in spite of the challenges in formulation development,
• The development of biosimilar formulations is expanding rapidly due to the anticipated patent expirations of many biologics,
• The U.S. FDA defines a biosimilar as a “biological product that is highly similar to the reference product notwithstanding minor differences in clinically inactive components and that has no clinically meaningful differences in terms of safety, purity or potency from an existing FDA-approved reference product”.

References

Ionova Y, Wilson L (2020) Biologic excipients: Importance of clinical awareness of inactive ingredients. PLoS ONE 15(6): e0235076.

Weiler, N (2020) Some Inert Drug Ingredients May Be Biologically Active. Comprehensive Laboratory Study Flags Drug Components in Need of More Rigorous Review, July 23, 2020. Link: https://www.ucsf.edu/news/2020/07/418146/some-inert-drug-ingredients-may-be-biologically-active. Accessed on 20/05/2022.