August, 2010
Regulation of Pharmaceutical Ingredients
Irwin Silverstein, IPEA Vice President and Chief Operating Officer
Abstract:
This article briefly describes the regulatory oversight by FDA for the manufacture of drugs. Increasingly, pharmaceuticals and their ingredients are being produced outside of the U.S. Manufacture in developing countries is the current trend for both drugs and their components. However the resources of FDA are stretched thin, diminishing their ability to provide adequate regulatory oversight. Both the pharmaceutical and ingredient industries are moving to address this gap in regulatory inspections and thus safeguard the U.S. drug supply.
Glossary:
Active Pharmaceutical Ingredient (API): Any substance or mixture of substances, intended to be used in the manufacture of a drug product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure or any function of the body of man or animals.
Components: Any ingredient intended for use in the manufacture of a drug, including those that may not appear in such drug.
Drug: defined in the Food Drug & Cosmetic Act as:
(A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and
(B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and
(C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and
(D) articles intended for use as a component of any article specified in clause (A), (B), or (C).
The term drug product is also used.
Excipient: Substances other than the API which have been appropriately evaluated for safety and are intentionally included in a drug delivery system.
Good Manufacturing Practices (GMP): Regulatory requirements for the quality system under which drug products and their ingredients are manufactured. The term current Good Manufacturing Practice (cGMP) is also used.
IPEC-Americas: A trade association comprised of excipient manufacturers and pharmaceutical companies with the mission to assure the safety of excipients.
Regulation of Drug Manufacture
Components of drugs are defined as drugs in section 201(g)(1)(d) of the Food Drug & Cosmetic Act (21 U.S.C. 321) . According to section 501(a)(2)(B) of the Act, drugs and their components must be manufactured in accordance with cGMP.
Since 1979 drug product manufacturing has been regulated by the Food and Drug Administration under the Code of Federal Regulations (CFR) Title 21, Food and Drugs. Conformance to the requirements of Good Manufacturing Practices (GMP) is described in many FDA Guidance documents, trade journals, and books.
Drugs are often referred to as drug products, dosage forms, or finished pharmaceuticals and are comprised of both active and inactive ingredients; which collectively are referred to as components. The Active Pharmaceutical Ingredient (API) is the agent intended to furnish pharmacological activity for the diagnosis, cure, mitigation, treatment or prevention of disease or to affect the structure or any function of the body of man or animals. The remaining components are inactive ingredients called excipients. Excipients include; colors, flavors, sweeteners, tablet binders, disintregants, coatings, capsules, printing inks, flow aids, processing aids, preservatives, etc. The cotton that was once used in pill bottles to keep the tablets from abrading was considered an excipient at one time.
While 21 CFR ¶210 and 211 establish the GMP requirements for the manufacture of finished drugs, the FDA has issued no regulatory requirements for GMP under which drug components are to be manufactured, either the API or excipient. Recently, the FDA adopted ICH Q7 as guidance for manufacturing the API and inspects API manufacturing sites accordingly. While the FDA has not formally adopted any GMP requirements for the inspection of excipient manufacturers, FDA inspectors generally refer to the IPEC-PQG guide first issued in 1995 by International Pharmaceutical Excipients Council of the Americas (IPEC-Americas), an industry trade association. Whereas there is a large body of literature as a resource for complying with cGMP by manufacturers of drugs, there is comparatively little for producers of drug components.
As noted, drug manufacturers are to conform to cGMP; where the “c” is short for current as in current Good Manufacturing Practices. GMP establishes the requirements for the quality system under which drugs and their components are to be produced. The “c” in cGMP puts the industry on notice that the FDA expects each company to implement any improvements to GMP that have been published in the literature or otherwise established by FDA. Thus GMP requirements are in a constant state of improvement.
Approval of Drugs
When a prescription is written, it is usually for a specified dosage of API generally in milligram quantity, e.g., 10mg Lipitor. Since the drug product is often on the order of a gram in weight, it is clear that the vast quantity of the drug product often is comprised of excipients. It is quite common for a drug product to contain 6 or more excipients to facilitate the storage, delivery, and stability of the active ingredient to the patient via the designated route of administration e.g. oral, topical, etc. and bioavailability in the patient e.g. adsorption through intestinal wall.
The development of a new drug generally begins with FDA review and approval of an Investigational New Drug (IND) application requesting use in clinical trials of a new active ingredient in an experimental drug formulation. New drugs are approved by the FDA after review of clinical data and other pertinent information submitted in a New Drug Application (NDA).
Generic drugs are approved for use in the U.S. with FDA approval of an Abbreviated New Drug Application (ANDA). Generic drug safety and efficacy is based upon the approved NDA. A principal concern of the FDA is assurance the generic drug formulation displays the same bioequivalence as the branded drug. Note that the generic drug manufacturer may use excipients from manufacturers who are not the same as those used by the brand name company. The composition of those excipients are probably somewhat different.
In conjunction with the review of the NDA or ANDA, the FDA performs a Pre-approval Inspection (PAI) of the drug manufacturing site. In addition to the inspection of the drug manufacturer the FDA also performs a PAI of the site that produces the API. Note however that there is almost never an inspection by the FDA of the manufacturers of the other drug components, the excipients.
TABLE 1
Number of Drugs Manufactured at Foreign Sites Has More Than Doubled Since 2001
The FDA has made a commitment to Congress for routine inspection of domestic drug manufacturers every 2 years. However, as reported in the NY Times, the FDA conducts foreign inspections of drug manufacturers approximately once every 13 years. Table 1 illustrates the rapid increase in the manufacture of drugs and APIs overseas and the trend is accelerating.
Economic developments in the manufacture of drug products and the API have resulted in production relocating from the U.S. and Western Europe to developing countries such as India and China. Inspection of those drug product and API manufacturing facilities has thus become more complicated for the FDA. Recently, the FDA has begun opening foreign offices and adding inspection staff to improve the frequency and efficiency of overseas inspections. Thus the frequency of inspection is poised to begin increasing substantially.
While the FDA is intent on inspecting the manufacturers of drug products and APIs every couple of years, there is no similar intention to inspect excipient manufacturers. The FDA generally only inspects excipient manufacturers, domestic or foreign, if risk to patient safety is attributed to an excipient or if a new excipient has been introduced. Thus seldom is there an audit of an excipient manufacturer.
All sites that produce drug product and API in the U.S. or intended for import into the U.S. must register with the FDA. However there is no registration requirement for the manufacturers of excipients! Thus the FDA has no direct knowledge of who is producing an excipient or where it is manufactured. Also the FDA has no knowledge of the quantity of excipients that are imported into the U.S. for use as pharmaceutical excipients. U.S. Customs does not keep such records.
Recent incidents of Economically Motivated Adulteration, a term coined by the FDA, have involved the substitution of Oversulfated Chondroitin Sulfate for Heparin (an API), diethylene glycol added to the more expensive sweetener glycerin or propylene glycol (excipients), and melamine added to milk and milk products to mask their dilution with water. Table 2 illustrates the chemical similarity between the excipients glycerin and propylene glycol and the poisonous antifreeze diethylene glycol.
While the melamine contamination was in a food, it demonstrated to the FDA that there was a potential for similar adulteration of certain excipients. The origin of each of these adulterated ingredients was traced to manufacturers in China. Both the FDA and pharmaceutical industry were alarmed by these episodes and the deaths they caused overseas. It has also caused Congress to begin consideration of measures to protect the U.S. public.
TABLE 2
It is the responsibility of the pharmaceutical manufacturer to assure the ingredients they use are produced in accordance with cGMP and meet quality requirements. Therefore major manufacturers, both brand name producers and some major generic manufacturers, have active audit programs to visit not only the API manufacturer but also excipient suppliers. Cost constraints would seem to be preventing most generic manufacturers from similarly auditing their suppliers, especially excipients.
It is likely that excipient manufacturers in developing countries are not audited by their customers since their excipients are more likely used by generic manufacturers rather than brand name producers.
A Congressional committee has been considering mandating FDA inspection of excipient manufacturers. However there are far more excipient manufacturing sites than there are producing drugs or APIs. Clearly, such a mandate would be unrealistic since FDA resources are not sufficient to inspect overseas drug and API manufacturers.
The solution to the problem of excipient supplier auditing is to either share audit reports or rely on certification to assure the excipient supplier is in adequate conformance with cGMP. International Pharmaceutical Excipients Auditing (IPEA), a subsidiary of IPEC-Americas, has been performing audits of excipient suppliers since 2001 as a substitute for the audit ordinarily performed by the pharmaceutical customer. Rx360, a consortium of pharmaceutical and component manufacturers, is initiating a program to share audit reports performed by member company auditors. Audit reports by either organization thus provide the drug manufacturer with a basis for qualifying their supplier.
The United States Pharmacopeia (USP) has developed a more comprehensive program called USP Verified Ingredient. In addition to auditing the component manufacturing facility, the USP reviews component manufacturer’s chemistry, manufacturing, and controls and also samples and tests the ingredient. Customers that purchase USP Verified components have confidence the ingredient was produced according to cGMP and should meet quality requirements.
The FDA recognizes that certification of ingredient manufacture enhances the shared audit approach by using a more comprehensive audit as the basis for certifying the component supplier is in substantial conformance with cGMP. IPEA has been seeking accreditation by the American National Standards Institute (ANSI) for their Excipient GMP Conformance Certification program. Since ANSI is the recognized U.S. authority for accreditation, it would allow the FDA to rely on IPEA certification of excipients to help FDA meet the Congressional mandate under consideration for regulatory inspection of all excipient facilities.
Pharmaceutical components are increasingly manufactured in developing countries making regulatory oversight difficult. Recent incidents have demonstrated the importance of assuring all manufacturers comply with U.S. requirements. Industry has recognized the risk and has begun implementation of measures to assure all ingredients are suitable for use in drug products.
Until there is adequate oversight of drug and ingredient manufacture, I am cautious about who manufactures drugs my family uses; especially generic drugs. Comfort with the drug manufacture can be gained through a quick internet search of the manufacturers’ website. Assurance is provided by manufacturers that:
1. Produce their drugs in the U.S., due to the enhanced regulatory oversight,
2. Are sufficiently large to have a staff of supplier auditors, and
3. Don’t create the impression they are a U.S. company when the only U.S. operation is an office.
Irwin Silverstein, IPEA Vice President and Chief Operating Officer, is a consultant specializing in quality assurance and regulatory compliance for pharmaceutical excipient ingredients. He also has experience in areas of quality assurance for API, medical device and drug products. He was the Director of Corporate Quality Assurance for ISP and has recently been a consultant to pharmaceutical firms who have entered into Consent Decrees with the FDA.
