White Paper –
An Explanation of IPEC Guidelines

Patty Benson, Director of Quality Assurance at SAFC explains what IPEC is, their guidelines and why SAFC is using it as a basis for its new GMP offering to biopharmaceutical manufacturers.

Background
Regulation by Proxy
The Benefits of Compliance by Choice
SAFC’s Approach to IPEC

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Background

The required standards for manufacturing active pharmaceutical ingredients (APIs) are laid out in GMP (good manufacturing practice) requirements. All competent API manufacturers are well aware of these guidelines and must adhere to them, but they only apply to the API and not the excipient. These non-active ingredients (excipients) are also critical to drug product manufacture and thus must be controlled. Unlike API’s, there is no formal regulation for excipient manufacture, however, the International Pharmaceutical Excipients Council (IPEC) has developed a comprehensive guideline to assist manufacturers in controlling excipients. These guidelines, along with regulations such as 21CFR 820 can be used as the basis for a supplier’s overall approach for providing high quality, well documented critical raw materials for the pharmaceutical and biopharmaceutical industry.

IPEC is a regional industry association of excipient manufacturers, active in four regions: the US, Europe, Japan and China. These four regional groups focus on locally applicable laws, science and general business practices. There are several IPEC guidelines, covering topics such as good manufacturing and good distribution practices, and it also provides a set of audit templates, giving auditors directions that ensure audits are consistent.

The IPEC guidelines were first established more than a decade ago, based on work going back to the 1990s in Europe, and have been updated from time to time since then. Originally the guidelines were written by industry members and agreed on by excipient manufacturers; they state what excipient suppliers believe they should be doing and what should satisfy drug product manufacturers. In simpler terms, the IPEC guidelines are used by the drug product industry to set out what an excipient should look like in terms of quality. Conversely, they are used by excipient manufacturers to enable them to identify what customers and regulators are looking for in a product. Rather than having to comply with a multitude of different quality systems from many different drug product manufacturers, they provide a single set of informal standards as a basis to work from.

Regulation by Proxy

It is to be noted that these are not a formal set of standards to which companies must adhere. Instead, the IPEC guidelines work as a proxy, and drug product manufacturers expect excipient suppliers to meet the general controls. This is an important distinction: many of the companies who make excipients are not dedicated pharmaceutical ingredient manufacturers. Rather, the vast majority of their production is destined for the food industry or general chemical use, and if the formal requirements become too onerous, they will be tempted to walk away from the business. The cost of formal compliance would simply not be worth their while for the small proportion of the business pharma represents.

While there are no formal regulations, there is an industry expectation that excipients should be manufactured under GMP conditions. However, unlike APIs where the GMP is legally enforced by the regulators, here the enforcement is generally being done by the drug product manufacturers themselves. The IPEC guidelines provide a baseline to operate from and are essentially a combination of the relevant parts of ISO 9001 and ICH Q7 guidance for API manufacture.

The backbone of the guidelines mimics ISO 9001, which the majority of chemical manufacturers already have in place and there are only a handful of additional requirements more specific to the excipients sector. The aim is to provide a harmonized set of standards, so the excipient manufacturer knows what to expect when they are being audited by a drug product manufacturer, and the drug company is not surprised by what they see during the audit. It serves as a tool for the excipient manufacturer to make a consistent product, every time.

In terms of quality standards, there is an expectation that excipients will be pure, but the guidelines do not go to the full length that the ICH Q7 guidance does in terms of formal validation for processes and cleaning. This does not mean there is no need for validation. In fact, there is still the expectation that there will be systems in place to ensure that product carryover does not occur and that processes are run consistently.

The Benefits of Compliance by Choice

As they are not formal standards, how can manufacturers show they comply with the IPEC guidelines and assure pharma companies can buy safely from them? Essentially, it is a case of carefully reading the appropriate standards, and identifying the standards they need to meet. They then have to define how to reach them, and put in place whatever programs are necessary to ensure that they get there. A quality-focused company will likely have much of this already in place, and be used to carrying out internal audits as this is a requirement of ISO 9001. By marrying up what they already do to what is stated in the guidelines, they can assure customers that they are in compliance during an audit.

A valuable tool offered by IPEC is its joint audit service. A certification process is carried out on an excipient manufacturer, and these audit reports can be shared. This helps minimize costs for both the excipient manufacturer and the drug product manufacturer. Rather than many different drug product manufacturers visiting with the same questions, they can see a copy of the IPEC audit report which will answer many, if not all, of their queries.

It is very important that excipient manufacturers base their production standards on the IPEC guidelines, even though they are not formal standards. Excipients are present in the final drug product, and contaminated products must not reach patients. The IPEC guidance helps to ensure minimal contamination and consistent product. High-profile contamination issues have made both drug product manufacturers and regulatory agencies much more sensitive to the possibility of contamination, whether intentional or unintentional. The authorities in Europe, and to a growing extent in the US, are looking for drug product manufacturers to be in control of their entire supply chain, to understand what their excipient manufacturers are doing, how they control their processes, and what are the potential contaminants and impurities.

SAFC’s Approach to IPEC

SAFC is now moving to ensure that its new PharmaGrade portfolio of critical raw materials, which are targeted for use by small molecule and biopharmaceutical manufacturers, are made in accordance with the IPEC guidelines. In line with many other companies, SAFC is looking at IPEC as an excellent guidance document, and something that adds value to the manufacture of both drug products and excipients. Even if a product is not destined for use as an excipient, the guidelines provide a robust basis for ensuring quality, whatever the end-use may be.

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