USP/PDA Co-sponsored Conference:Residual Solvents

January 18–19, 2007

Excipients Manufacturer Perspective

David R. SchonekerChair – IPEC Americas

IPEC Supports ICH Q3C & USP

IPEC supports and agrees with implementation of ICH Q3C and the related USP <467> General Chapter and General Notice for the control of Residual Solvents in Drug Products

These guidances do not preclude the use of the listed solvents or set up regulatory compliance limits for residual solvents in excipients themselves but rather in the drug product based on exposure limits

IPEC Supports ICH Q3C & USP

These guidances do not specifically address solvents deliberately used as excipients as well

They recognize that solvents may sometimes be a critical parameter in the synthetic process for manufacturing an excipient and that the presence of certain residual solvents in an excipient may impact excipient functionality

Monograph References

IPEC strongly objected to the original approach used by USP to list a Residual Solvent requirement in each excipient monographThis would have created confusion about what would be necessary for an excipient to be considered to be of compendial gradeWould have created controversy when using Excipients which exceed the concentration limits listed for Class 2 solvents

Monograph References

IPEC worked with PhRMA in late 2005 to convince USP to “Retract” the monograph listings in the USP/NF that were due to go into effect on Jan. 1, 2006

USP published a retraction but unfortunately <467> was already listed in the excipient monographs in the published USP/NF text due to publication schedule

This has created significant confusion throughout industry

Typical Practices

Generally, Class 1 solvents such as Benzene are no longer typically used in producing pharmaceutical grade excipients.

However, historically some excipients were made with Class 1 solvents and some grades may still be made with these solvents, especially non-pharma grades

Many excipients are manufactured using Class 2 and Class 3 solvents

Areas of Confusion

The Concentration Limits listed in the Class 2 Solvent Table are not specifications for the level of a given residual solvent that is acceptable in an excipient

These levels refer to what is acceptable in the pharmaceutical product itself based on exposure calculations

Excipients sometimes exceeding these levels are commonly used in drug manufacture

Examples of Excipient Residual Solvent Content

PovidoneMay contain formic acid from the manufacture of PVP

HypromelloseMay contain methanol which can either be used in the manufacture of HPMC or produced as a by-product during manufacturing

Polyethylene GlycolMay contain residual 1,4 dioxane and ethylene glycol which is used in the manufacture of PEG

Examples of Excipient Residual Solvent Content

Sodium CarboxymethylcelluloseMay contain methanol and 2-propanol which is used in the manufacture of Socium CMC

Sodium AlginateMay contain 2-propanol which is used in the manufacture of Sod. Alginate

Xanthan GumMay contain 2-propanol from the manufacture of Xanthan Gum

Examples of Excipient Residual Solvent Content

Polysorbate 80May contain residual 1,4 dioxane and ethylene glycol which is used in the manufacture of Sodium Alginate

LecithinMay contain acetone which is used in the manufacture of lecithin

EthylcelluloseMay contain toluene which is used in the manufacture of ethylcellulose and ethanol and diethyl ether produced as by-products during manufacture

Examples of Excipient Residual Solvent Content

Hydroxypropyl CelluloseMay contain acetone and heptanewhich are used in the manufacture of HPC

TriacetinMay contain acetic acid which is used in the manufacture of triacetin

Polyvinyl AlcoholMay contain methanol and methyl acetate which are used in the manufacture of PVA

Examples of Excipient Residual Solvent Content

GlycerinMajor supplier of Glycerin confirmed that only Class 3 solvents likely to be present but stated that the names of the solvents used or generated in their process are considered proprietary informationThis type of information may create problems for users to assess their need to test routinely for all the Class 3 solvents

Areas of Confusion

Elimination or lowering the levels of certain residual solvents in some excipients may significantly change the quality and performance of the excipient for certain functions

The types and levels of residual solvents present in an excipient may vary greatly from one manufacturer to another based on their specific process and this must be considered when evaluating alternative sources

Reduced Testing Options

The drug manufacturer may be able to limit the amount of testing they must do on the finished drug product if all excipients and API’s used are below the listed limits in the table

Therefore, to take advantage of calculation options and reduced testing requirements, it is more important than it was in the past for pharmaceutical users to better understand how their excipients are manufactured

Information Sharing

There will need to be a good information exchange of typical excipient residual solvent levels between user and maker for this to be successful

This may not be easy due to confidentiality concerns and the fact that many excipients are not produced primarily for the pharmaceutical industry

Pharmaceutical Excipients

A very diverse collection of materials from many originsAbout 1200 to 1300 excipients in use in marketed pharmaceutical products (not counting colors and flavors)Only about 300 to 400 currently have monographs defining quality standards in various pharmacopeiasSome monographs may contain tests and limits for certain key residual solvents known to remain after the manufacturing process that may have safety implications

Excipient Composition Profile

The overall definition of the substance composition is very importantNeed knowledge of origin and main use of the excipient to assess the significance of impurities including residual solventsDifferentiate between intrinsic composition, impurities and additivesExcipient impurities must be evaluated differently than impurities in APIs

Excipient Composition Profile

Excipients frequently function because they are not “pure”

…..and that is not a “bad” thing!!

What might be contained in an Excipient?

The ‘nominal’ chemical componentImpurities

OrganicInorganic

Processing aidsAdditivesResidual solvents/waterOther (concomitant) components

Essential for performance (functionality) in some way

Actions Underway

IPEC is developing a guideline on excipient composition which will address all aspects of composition including residual solvents, additives impurities, processing aids and related issues IPEC is working with PDG to develop appropriate definitions and policies so that all Pharmacopeias can attempt to treat excipient composition issues in a harmonized manner

Actions Underway

IPEC has recently published an Excipient Information Protocol (EIP) Guideline which provides a standardized approach which can be used for information sharing for residual solvent information as well as much other excipient information

MSDS Style conceptIncludes Change ControlEliminates the need for questionnaires

Better Communication

Better confidentiality agreements will need to exist between excipient makers and users for the makers to share their residual solvent information since this type of information may be competitively sensitiveThese agreements need to be proactively developed to minimize time delays on sharing the information

Actions Underway

IPEC has recently published an Excipient Master File Guideline which can be used to supply confidential information to regulators to support drug registrations when there may be significant competitive concerns which prevent sharing of certain information through use of confidentiality agreements

Better Communication

Users will need to develop improved relationships with their suppliers to insure trustMore efforts will be needed to evaluate equivalency of alternate suppliers during excipient qualification exercises

This must go beyond compendial testingMust address functionality implications and stability

Primary control of user excipient selection decisions needs to be taken out of the hands of supply chain departments and placed back in the hands of technical and quality groups

Questions

How does your company assess and discuss residual solvent issues with your suppliers?

Is it a “TWO-WAY Street”??

Win-Win Communication will be absolutely necessary for pharmaceutical companies to obtain the information they need

Are you working with excipient suppliers who understand these issues and are prepared to discuss them scientifically given appropriate confidentiality protection??