Saturday, December 24, 2011

Regulatory aspects of pharmaceutical excipients

Pharmaceutical excipients are inert substances used as diluent/Vehicle/Fillers/Binders/bulk agent/lubricants for drug formulation. They are responsible for product performance and enable the drug to give desired pharmacological action. The regulatory guidelines have made it mandatory that all constituents of a drug formulation should be compliant and tested as per current cGMP regulations for safety and efficacy of drug. Increasing focus on excipients is due to past incidents, where patients had died due to contaminated excipients, used by pharma companies. It is the responsibility of the pharma manufacturer suppliers to use high quality pharma ingredients in the respective formulation.
Regulatory bodies governing the standards of excipients are as per international and national guidelines. International guide lines are as per ICH Q7A GMP applicable to API's. Use of any new excipient in formulation should be assisted with quality and safety data.
Excipients are classified as per the source of origin:
1.Animal origin
2. Plant origin
3. Mineral origin
4. Synthetic origin
Risks associated with non-GMP manufactured excipients
Documented evidence:
Fraudulent product obtained from broken supply chain and distribution routes leading to contamination cases:
1990 Nigeria: Cough syrup contaminated with solvents (47 reported deaths)
1986-1998 India and Bangladesh: Paracetamol syrup contaminated with diethylene glycol from propylene glycol origins (236 reported deaths)
1996 Haiti: Glycerine contaminated with diethylene glycol (88 reported deaths)
Adulterated excipients causes failure of drug batches during manufacturing and may also result in hazardous products and thus it is risky for drug manufacturers and the patients.
Thus due to the above associated risks and subject to mandatory requirements, excipients must be manufactured, processed, packaged and held in conformity with Current Good Manufacturing Practice (cGMP).
Excipients with cGMP Conformance should be based on ICH Q7A GMP Guidance for APIs as regulatory bodies have not developed regulations or specific guidance on cGMP conformance for excipients. However, FDA is supportive of the IPEC GMP Guide for Bulk Pharmaceutical Excipients. Quality characteristics of excipients are significant to the overall quality of the drug products in which they are used.
Drug product manufacturers rely on excipient manufacturers to provide excipients of uniform quality, physical and chemical characteristics, eg., levels of impurities.
As per 21 CFR 211.84(d)(2), the user/drug product manufacturer is required to test every batch of drug excipient for conformity with written specifications, for purity, strength and quality. However, drug product manufacturers can rely on their suppliers for this testing, provided that the reliability of the suppliers' test results is validated at appropriate intervals
The most important thing to note is that testing as per USP/NF/BP/Ph Eur does not replace compliance to GMP.
Regulation of excipients
Excipients can be classified as official in pharmacoepia or non official in pharmacoepia. Compendial excipients have composition consistent with monographs published in compendia such as USP-NF, BP, Ph Eur, and JP. The non pharmacoepial excipient usage should be justified with safety and quality data.
Increasing focus on excipients is based on several parameters:
1)Excipients help deliver final drug formulation performance and are also considered to be major part of the formulation
2)As per the cGMP, quality can be introduced in final formulation, and thus GMP is applied right from incoming of materials to distribution in market
3)Understanding variation of excipients properties as they relate to product quality attributes
4)Building robustness and flexibility into manufacturing process
5)Lack of guidelines Specific to Excipients
US-FDA perspective
An excipient is defned by the US FDA as ''any component of a drug product other than an active ingredient''. In the US, the FDA assesses and permits use of excipients as part of a New Drug Application (NDA). In the US guidelines relating to preclinical data for NDA submission, excipients are not mentioned. Under US law, a new pharma excipient, unlike an active drug, has no regulatory status unless it can be qualified through one or more of the approval mechanisms available for components used in ?nished drug dosage forms.
EU - EMEA perspective
Within the EU there is a directive that makes it clear that new excipients will be treated in the same way as new actives. In Europe, the need for companies to fully consider the types of excipients in new drug formulations has been the focus of a guideline released recently by the European Commission on drug label and package leaflet excipient information for all MAA. This guideline indicates that all excipients must be listed on the drug label for parenteral, topical, inhalation, and ophthalmic products. For other medicinal products, only those excipients with a defined and recognised action of effect need to be declared on the label. In drug package leaflets, all excipients must be included. European regulations and guidelines also require that a full statement of the excipients used be given in the Summary of Product Characteristics (SPC) document for new drug formulations.
Japan - MHW perspective
The formal structure for regulating pharma excipient is quite complex. Responsibilities are divided among several divisions in the MHW and National institutes for Hygienic Sciences (NHS) and Central Pharmaceutical Affairs Council (CPAC) play key roles in the regulation of excipients.
There are two compendia containing monographs that describe Japanese standards for pharma excipients.
  • Pharmacopeia of Japan (JP)
  • Japanese Standards of Pharma Ingredients (JSPI)
Excipient evaluation
Excipients are important in assuring drug product quality and stability. Understanding and controlling the functionality of excipients can lead to more robust, flexible processes. Excipient specifications should be appropriate to assure product performance. Continual monitoring can assist in continual assurance of product quality. Understanding variation of excipient properties as they relate to product quality attributes are dependent on following parameters:
  • Particle morphology, powder property, polymorph, Hygroscopic, aqueous solubility and density
  • Identity, purity, incompatibility with drug substance or other excipients
  • Flow ability, compressibility
Excipient evaluation for a drug formulation should be based on following approaches:
Drug-Excipient Compatibility
Advantages: Maximised stability of a formulation, enhanced understanding of drug excipient interactions
Formulation Robustness
Advantages: Desired pharmacological action achieved, facilitates the development of novel drug delivery systems
Advantages: Minimises formulation processing problems, facilitates safer/more efficient manufacturing processes
Excipient supplier qualification
Apart from the above facts, it is very important that the pharma manufacturer, during sourcing of excipients for drug formulation should qualify the vendor on the following parameters:
1. A comprehensive assessment of
  • Excipient quality
  • The manufacturing process to make the excipient
  • The distribution controls used to deliver the excipient to the drug product manufacturer
2. Supplier systems and capability
3. Physical audit at manufacturing site
The purpose of this qualification is to ensure that the safety of the drug product is not compromised by the excipient. Both manufacturing (GMP) and distribution (GDP) aspects need to be covered. Failures at any point in manufacturer in the supply chain may put patients at risk. The modern pharma paradigm requires a Quality by Design (Qbd -ICH Q8) and a risk management approach (ICH Q9) to determine the details of that qualification. Those excipients posing the greatest risks require the most thorough controls.
Industry formed committees /Groups
1. EFCG — European Fine Chemical Group
4. COUNCIL America
6. European association of chemical distributors
7. The Pharmaceutical Quality Group
8. Rx-360 Mission
Advancement of industry initiatives
Pharma excipients have no official regulatory status independent of the finished dosage form in which they are used. As a result, the mechanism for regulation of these ingredients is not fixed.
Excipients form an integral part of medicinal products deserving quality management systems and appropriate regulations. Thus the days of treating excipients like commodities and buying them without fully qualifying the source and the entire distribution chain are over. Some excipients are also being used as API's by pharma companies when they were never intended by the manufacturer to be an API grade and are not made in an FDA registered facility using ICH Q7A GMP guidelines.
This adds to the risk of the pharma company and poses a safety risk to patients. Pharma companies need to take steps to guard against such practices and reduce their risk at all stages of the manufacturing process, even the processes that take place outside their premises. In the light of more stringent regulatory practices, and more complex supply chains, finding the right excipient manufacturer thus takes on additional significance.

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