The CDE article is a small auxiliary material, and the wrong use can also lead to life!

Original title: "Strategies for Risk Assessment and Management of Pharmaceutical Excipients" (with deletions)

Source: "China Pharmaceutical Industry Journal"

Authors: Ma Junwei, Anna (Center for Drug Evaluation, State Drug Administration)

In the new version of the "Drug Administration Law", the definition of "excipients" is: excipients and additives used in the production of drugs and the preparation of prescriptions
.

Except for the active substance ingredient (API), all medicinal components of the formulation are excipients
.

The functions of excipients include improving bioavailability, achieving specific release and delivery, optimizing production processes, enhancing drug stability, enhancing drug identification, and improving patient compliance
.

Excipients are an indispensable part of pharmaceuticals, and usually the dosage of excipients is significantly higher than that of API, and can account for up to 99% of the total mass of the preparation
.

The effect of excipients on the release, absorption, accumulation and clearance of API is directly related to the efficacy and safety of the drug
.

For a long time, people have generally neglected the control of the risk of excipients, causing many incidents of drug toxicity of excipients:

After the enterprise changed the excipient dehydrated calcium sulfate in phenytoin sodium capsules to lactose, the bioavailability of phenytoin sodium would increase and cause poisoning;

Paracetamol syrup contaminated with diethylene glycol (DEG) as the excipient propylene glycol resulted in the death of several children from acute renal failure (in the 2006 “Qi Er Yao” drug injury incident in China, 11 people died due to DEG pretending to be the excipient propylene glycol)
.

In response to domestic excipient safety issues, in 2006, the former State Food and Drug Administration issued the "Quality Management Practice for Pharmaceutical Excipients Production", which requires excipient manufacturers to implement quality management to ensure that excipients have the proper quality and safety
.

In 2016, the EU published the guidelines of 19 March 2015 on the formalised risk assessment for ascertaining the appropriate good manufacturing practice for excipients of medicinal products for human use as a GMP appendix, requiring marketing authorisation holders (manufacturing authorisation).

In 2017, with the support of the European Federation of Pharmaceutical Industries and Associations (EFPIA), the International Pharmaceutical Excipients Consortium of Europe (IPEC-Europe) and the Pharmaceutical Quality Group (PQG) developed a risk assessment model for excipients ( Figure 1)
.

ICH Q9 defines risk as "the combination of probability of occurrence of harm and severity of harm", and this model combines the basic principles of ICH Q9 with the specific requirements of risk assessment guidelines
.

The excipient risk assessment process emphasizes the close cooperation between the excipient user and the excipient manufacturer in the assessment process
.

1 Basic considerations for risk assessment of excipients

Risk assessment and management of excipients should be based on scientific knowledge, with a focus on protecting patients
.

At present, China only proposes specific GMP requirements for excipient manufacturers to ensure the quality of excipients, but has not yet established a complete risk assessment system and guidelines for excipients, especially for MAH
.

Based on the EU guidelines for risk assessment of excipients and the evaluation principles of existing industry associations, this paper starts from the actual clinical medication directly related to patients, and takes the specific application of excipients in preparations as the entry point.
The daily dosage and excipients functional correlation indicators (functionality-related characteristics, FRC) four aspects are discussed for risk assessment, which can provide reference for the risk assessment of excipients
.

1.
1 Route of administration

The same excipient can be used for preparations of different administration routes, but the influence of excipients on patients receiving different administration routes is different
.

For example, antioxidants in injections that do not perform their intended function are more harmful than in creams
.

The IPEC ranks excipient risks by route of administration as follows: topical < oral, vaginal and rectal < pulmonary, inhalation < parenteral, ophthalmic and open wound
.

During the registration and filing of excipients in China, pharmaceutical excipients used for injections, ophthalmic preparations, and inhalation preparations are defined as high-risk excipients
.

Therefore, when selecting excipients, the risk level should first be determined according to the route of administration.
For preparations used for injection, ophthalmic use, inhalation and open wounds, the excipients in the preparations are all high-risk excipients
.

It should be noted that the excipients used for injection, ophthalmic, and open wound routes must be sterile, and the injection solution must carry out endotoxin control of the excipients
.

To evaluate the consistency of the quality of excipients before and after the change of high-risk excipient suppliers, it is recommended to evaluate from the aspects of preparation process, internal control standards, impurity level, and microbial level
.

Attention should be paid to the quality assessment of functional excipients that affect product safety and efficacy
.

The polymers used in eye drops (such as gellan gum, hydroxyethyl cellulose and other excipients can play a role in adjusting the viscosity of the liquid medicine, and there is a correlation between the viscosity and the retention performance of the liquid medicine in the body
.

Even if the excipients from different suppliers meet the Pharmacopoeia standards, there may be some differences in the degree of polymerization of such excipients.
Special attention should be paid to the influence of the relative molecular mass of the polymer on the viscosity of the liquid medicine
.

1.
2 Drug population

Excipients used in medicines for children, pregnant and lactating women are also defined as "high risk" excipients
.

Compared with adults, special groups such as children and pregnant women have stricter requirements on drug safety
.

This is mainly due to differences in the pharmacokinetics of drugs in children and adults, and even children of different ages
.

Benzyl alcohol is a preservative that is metabolized in adults to benzoic acid, which then combines with glycine to form hippuric acid for excretion
.

However , the low conversion rate of benzoic acid to hippuric acid in neonates can cause fatal metabolic acidosis, respiratory and central nervous system (CNS) depression and other adverse reactions
.

In the annex to the EU Guidelines on Excipients in the Label and Package Leaflet of Medicinal Products for Human Use, excipients such as benzyl alcohol, boric acid, cyclodextrin, propylene glycol and esters clearly give warnings for use in children
.

The excipients database (safety and toxicity of excipients for paediatrics) of the European Paediatric Prescribing Initiative (EuPFI) also contains some information on excipients related to the safety of medicines in children
.

In order to strictly control the quality and safety of excipients used for the above-mentioned special populations, the quality standards of excipients and the evaluation requirements of excipient suppliers can be appropriately improved
.

1.

The dosage is related to age, degree of disease progression,
etc.

The frequency of drug administration is different, and the daily intake of excipients is different; the higher the daily excipient dosage, the higher the possibility of adverse reactions and the higher the risk
.

It has been reported in the literature that the excipients are classified as low, medium and high risk according to the maximum dosage of the excipients
.

Low risk: The maximum daily dosage of excipients is within the maximum dosage range of the drug excipient database, such as the FDA inactive ingredient database (IID),
etc.

Moderate risk: By comparing the maximum daily use of excipients with one of the acceptable daily intake (ADI), tolerable daily intake (TDI), and no observable adverse effect level (NOAEL), when the dose differs by 100 It can be considered as a medium risk when it is more than 2 times
.

High risk: Refers to excipients for which there is no supporting data on safe dosage and experience with the route of administration
.

Excipient databases that may be used for excipient dosage assessment include the following
.

① IID  provides information on the dosage of the largest excipients in FDA-approved drugs, including excipient model, route of administration, dosage form, and the maximum dosage in a single dose, updated once a quarter
.

URL:

https://

The disadvantage of this database is that it does not reflect the number of daily medications, so it is impossible to determine the maximum daily dosage of excipients.

② Japanese Pharmaceutical Excipients (updated to 2016 edition) contains the existing pharmaceutical excipients, and confirms the route of administration and dosage;

"Specifications for Pharmaceutical Additives" (Japanese Pharmaceutical Excipients, updated to 2019 edition) contains the quality standards for excipients outside the pharmacopoeia
.

URL:

https://

In addition, the official website of the Japan Pharmaceutical Additives Association can inquire online information about the toxicity of excipients
.

URL:

https:// _ _

③ For excipients for topical route of administration , information on safety can be searched in the cosmetic ingredient review (CIR) database .

URL: https:// Because the routes of administration of topical drugs and cosmetics are relatively close, the existing information on excipients in cosmetics can provide certain safety support
.

The role of tert-butyl hydroquinone (TBHQ) in ointment is an antioxidant.
The data of TBHQ in the CIR database shows that TBHQ is used in at least 266 kinds of cosmetics at a concentration of 0.
1% to 1.
0%
.
In addition, the TBHQ dosage information in lipsticks can also provide some reference for determining its dosage in oral medicines
.

④  In the database of the Joint FAO/WHO Expert Committee on Food Additives (JECFA), ADI and safety assessment reports of some excipients are provided
.

URL:

http://

1.
4 Excipients Functional Correlation Index (FRC)

FRCs can have a significant impact on the critical quality attributes (CQAs) of the drug product
.

Some excipients can have a significant impact on drug efficacy.
For example, excipients with sustained and controlled release functions can significantly affect the release behavior of drugs in vivo.
Such excipients that affect the behavior of drugs in vivo are classified as high-risk excipients according to their functionality
.

If the excipients in the production of auxiliary preparations have an impact on the CQA of the drug, they are classified as medium-risk excipients according to their functions, such as changes in the type or proportion of tablet fillers that may affect the dissolution rate of tablets, etc.
;

Lubricants in tablets can smooth the production process, and also affect CQAs such as content uniformity and dissolution rate of the preparation, which may affect bioavailability, especially in low-dose solid dosage forms
.

Excipients that do not have a significant impact on product CQA are classified as low-risk excipients, such as pigments in coating materials
.

Excipients that are considered to be low and moderate risk based on functional assessment, should also be identified as high risk excipients if they are not listed in the Pharmacopoeia or listed in the Pharmacopoeia but have not been studied for FRC
.

Such excipients can be classified as low-risk excipients if the FRC is studied during drug development and its impact on product quality is determined
.

The United States Pharmacopoeia (USP) and the European Pharmacopoeia (EP) take 2 different approaches to FRC requirements
.

In the general chapter of USP1059 Excipient Performance , excipients are classified according to the function of different dosage forms, and the physicochemical properties and detection methods of such excipients that may affect the function are provided, such as particle size, bulk density, crystal form, particle size, bulk density, crystal form, etc.
of fillers in tablets and capsules.
moisture,
etc.
USP does not specify FRC checks in the text of excipients
.

EP lists FRC and testing methods in the text of some excipients , such as the viscosity of co-treated excipients with microcrystalline cellulose and sodium carboxymethyl sulfate as FRC index
.

In actual drug development and marketing production, there are changes in excipients, such as changes in excipient manufacturers, changes in excipient production processes, or differences between batches of excipients
.

These changes may have an impact on the physicochemical properties of excipients, such as the different physical properties and compressibility of microcrystalline cellulose in different production processes; the compressibility of lactose between different batches due to changes in crystal form; excipients between different batches Differences in reactive impurity levels have an impact on product quality,
etc.

MAH should focus on the risk of excipient change from an excipient functionality perspective
.
The marketing application should ensure the consistency or compatibility of excipients between key clinical batches and commercial scale-up batches, including the manufacturer, production process, and quality control
.

If there are significant differences in key excipients that affect product quality, a formulation bioequivalence study may be required
.

2 Thoughts on risk management of excipients

Risk management of excipients should be based on risk assessment
.

The quality management requirements of excipients and the management measures taken should correspond to the degree of risk
.

The risk of excipients should be managed throughout the life cycle, and MAH, excipient manufacturers or suppliers, and regulators should establish appropriate
excipient risk management systems

2.
1 MAH

The new version of the Drug Administration Law clarifies that the drug MAH is fully responsible for drug quality, including the safety and quality management of excipients
.

The EU Guidelines for Risk Assessment of Excipients emphasize that MAHs should conduct comprehensive and ongoing risk management for excipient manufacturers
.

Excipient quality control should meet appropriate GMP requirements, excipient management should be incorporated into MAH's drug quality management system, and excipient risk assessment documentation should be available on-site for review by GMP inspectors
.

MAH should have in-depth communication with excipient manufacturers or suppliers during the drug development process to complete the risk assessment of excipients in the drug product
.

The impact of high-risk excipients on product quality should be fully studied, and the quality requirements of excipients should be put forward in combination with their own product characteristics
.

Factors such as the source of excipients (e.
g.
animal, vegetable, mineral, synthetic), viral contamination, supply chain complexity, supplier history, packaging integrity, storage and shipping conditions need to be considered
.
Based on the assessment results, develop appropriate risk management measures, such as appropriate supplier audits, signing quality agreements, increasing FRC inspection requirements, and ongoing risk control plans
.

When a drug is submitted for marketing, high-risk excipients should establish a quality assurance system supervision mechanism with the excipient manufacturer
.

2.
2 Manufacturers or suppliers of excipients

The quality of the excipients is produced, and the excipient manufacturer needs to ensure that the excipients are manufactured to the appropriate GMP requirements
.

China has established a related review of original and auxiliary packaging, and manufacturers of auxiliary materials need to provide MAH with the authorization letter of use of auxiliary materials
.
The advantage of this policy is that it enables manufacturers of excipients to know the specific use of the excipients they produce, so the requirements for excipient manufacturers have been further improved
.

The original auxiliary package filing registration requires the auxiliary material manufacturer or supplier to submit an annual report.
If the product is changed, it needs to register the change information, inform the preparation manufacturer or MAH company, and write the annual report
.

Manufacturers of excipients should gradually accumulate basic experience in the actual use of excipients, and can provide usage advice to MAH when necessary
.

2.
3 Supervisors

It is recommended that supervisors strengthen management from the following four aspects
.

First, play a guiding role, encourage MAH and excipient manufacturers to establish the thinking of excipient risk assessment, fully learn from the management experience of international advanced regulatory agencies and industry organizations, and establish a scientific and effective excipient management system
.

Secondly, the intelligence and informatization of the auxiliary material filing and registration platform realizes a clear, complete and comprehensive management of the changes after the auxiliary material registration
.

Explore the establishment of a hierarchical management mechanism for excipient changes.
For excipient changes that may have a significant adverse impact on product safety and quality, timely warning and early intervention should be possible
.

In addition, the basic construction of the excipient database should be improved, and the information on the use of excipients should be updated and published in a timely manner based on the clinical use of drugs
.

Finally, it is recommended to publish the list of excipients with safety concerns in real time
.
Refer to the EU to provide possible safety issues of excipients in the drug insert
.

3 Outlook

Excipients are one of the important factors affecting product safety and efficacy
.

The establishment of scientific excipient management is an important topic, which should be completed in conjunction with excipient users, manufacturers, regulators and industry associations
.

Whether it is the use, production or supervision of excipients, awareness of risk assessment should be established, and “appropriate” management of excipients should be adopted
.