Are you ready?
By John Daniels
Changes to USP chapters have been implemented and more will be taking effect soon. These changes impact the routine operations of pharmaceutical and biopharmaceutical companies as well as those of their contract services and outsourcing partners. It’s important for pharmaceutical manufacturers to know and understand these USP chapter updates, and then to assess how their outsourcing partners — such as analytical services labs — are meeting these new requirements for regulatory compliance.
While there are continuous updates to the USP, there are three significant changes that require planning and careful coordination with contract service providers. The first involves USP <467> Residual Solvent Changes. The second and third changes are designed to harmonize USP General Microbiology chapters with the corresponding chapters in the European Pharmacopeia (EP) and the Japanese Pharmacopeia (JP). These harmonized USP General Microbiology chapters include USP <61> (formerly called the Microbial Limits Test) — which will be renamed the Microbial Enumeration Test — and USP <62>, a proposed new chapter created to describe requirements for growth and recovery of specified microorganisms such as Salmonella or S. aureus.
Let’s take a closer look at each of these USP chapters, along with some suggestions for making sure that you and your contractual partners are in alignment.
USP <467> Updates and How They Affect You
USP Chapter <467> Residual Solvent Changes went into effect on July 1, 2008. These updates have had a marked impact on U.S. manufacturers of pharmaceutical ingredients and products, as well as their outsourcing partners. Because of the complexity involved in addressing these changes, it’s essential that pharmaceutical companies understand these revisions, ensure they have the appropriate USP-compliant testing procedures, and validate that their materials satisfy the latest regulations.
Following are some guidelines to help contract pharma manufacturers — and their partners — address the new updates to USP Chapter <467>:
Identify which solvents are included in the expanded list of USP Residual Solvents
The list of solvents has been expanded to include all of the Class 1, Class 2 and Class 3 solvents noted in the International Committee for Harmonization (ICH) Q3C Impurities: Residual Solvents Guidelines. Class 1 solvents are known to cause unacceptable toxicities and should be avoided in the manufacture of drug substances, excipients and drug products. Class 2 solvents have less severe toxicity and their residuals in products should be limited as much as possible. Class 3 solvents are less toxic and should be used where practical.
Understand how USP Chapter <467> should be implemented with APIs, excipients and drug products
For regular updates and guidance, visit the U.S. Pharmacopoeia website at www.usp.org/USPNF. Another valuable resource is the International Pharmaceutical Excipients Council (IPEC) Americas website — www.ipecamericas.org — where you can download IPEC Excipient guidance documents related to Good Manufacturing Practices (GMP) and Drug Master File (DMF) protocols.
Apply the same USP principles to non-compendial drugs (drug products for which no monograph exists)
To assure safety, it is likely that the FDA will, across the board, expect all drug products to comply with USP <467> requirements. The FDA’s Office of Generic Drugs and the Center for Drug Evaluation and Research have already recommended this in practice.
Know how to account for those solvents not listed by the USP
If a residual solvent is not listed, then it is up to the drug product manufacturer to assess the safety data for the solvent and its implications in order to establish a safe use level. Periodically, the ICH and the USP will be updating the list to include additional solvents once they become aware of their use in pharmaceuticals. Manufacturers who find that they have solvents present which are not on the list should report this to ICH and the USP.
Recognize the differences between the new testing procedures (A, B or C) and determine which is appropriate for your pharmaceutical ingredient or product
For a material where the presence of Class 1 and Class 2 solvents is unknown, Procedure A is performed as a screening test. If no response for solvents detected in the sample exceeds those in the standard, the requirements of the test are met. If one or more of the solvent responses is equal to or exceeds the standard response, Procedure B is performed. Procedure B confirms the identity of any solvent(s) not meeting the requirements of Procedure A. If the identities of the solvents are confirmed, Procedure C is performed to determine the concentration(s) of the solvents.
Determine when to test and how often
Pharmaceutical manufacturers need to know at which stages within the production process — from raw materials to finished product — they should be testing for residual solvents. There are three things to consider: (1) Is testing product from stability studies a fair representation of fresh product that may contain higher levels of volatile solvents? (2) What assurance do you have that your product won’t be negatively impacted by future changes in suppliers or existing suppliers modifying their manufacturing processes? (3) Do you have procedures in place to recheck your finished goods periodically?
If you have an internal testing method, consider how to reconcile it with the USP guidelines
If you have your own methods for testing residual solvents, you need to ensure that they are fully validated and suitable for their intended use. These do not necessarily have to be the exact analytical methods specified in <467>, but they should demonstrate sufficient and adequate screening for residual solvents.
Clearly define the information you expect to receive from your suppliers, and decide if an audit is needed
Compliance with USP <467> is not necessarily mandated for your suppliers; therefore it’s in your best interests to have systems in place to evaluate the quality of your suppliers. The IPEC (www.ipecamericas.org) offers guidance for Excipient Qualification Programs and an Excipient Information Package (EIP) with standards for the exchange of data between excipient suppliers and excipient users. You should require that your supplier share residual solvent statements. To verify the supplier’s GMP and COA/regulatory claims, third party audits are advised. International Pharmaceutical Excipients Auditing, Inc. (www.ipeainc.com) provides audits that follow recognized IPEC, ISO, WHO, and USP principles of cGMP for excipient ingredients.
If you outsource to an analytical lab, evaluate how this contract facility is meeting the new USP residual solvent requirements
By now, most outsourced analytical laboratories should have implemented the new General Chapter <467> tests. These methods will initially have to be qualified for each sample to demonstrate that solvents can be appropriately recovered. Therefore, pharmaceutical manufacturers should contact their outsourcing partners to ensure they are able to meet the requirements of the new USP residual solvent changes in a timely fashion. Labs that got on board early with the USP changes will have more experience with the qualification process.
Preparing for Harmonized Microbiology General Chapters in the USP
Now that USP <467> changes are in effect, pharmaceutical and biopharmaceutical manufacturers and their partners should be planning for additional changes, namely USP <61> and USP <62> harmonized microbiology General Chapters. Ultimately, the goal of pharmacopeial harmonization is to promote consistency of microbiology methods used by companies globally. The original implementation date of August 1, 2007 has been postponed to May 1, 2009 due to extensive comments and concerns communicated to the USP. This revised date will correlate with the effective dates of EP and JP harmonized chapters.
There are a number of changes proposed in USP <61>. Formerly called the Microbial Limits Test, the chapter will be referred to as the Microbial Enumeration Test. The most obvious change is separation of the Absence of Specified Microorganisms test into a new chapter, USP <62> (see below). Following are further details on the anticipated changes for both USP chapters:
Changes to USP <61> Microbial Enumeration
USP <61> describes microbial enumeration tests, which are the plate count procedures for bacteria, yeast and fungi. Although the plate count procedure itself will not change, the incubation temperatures and times for bacteria will change slightly. Yeast and mold incubation temperatures and times will remain the same. A description of the membrane filtration method has been added and also more details for preparation of different sample types.
The preparatory test, now called the suitability test, has a more detailed methodology than before. In addition, the chapter includes more information on neutralization and removal of antimicrobial activity, but still acknowledges that not all products can be suitably neutralized and addresses how to proceed. Growth promotion requirements for media are also better defined in the harmonized chapter.
Addition of USP <62> Absence of Specified Microorganisms
The proposed USP <62> will be a new chapter and will describe requirements for growth and recovery of specified microorganisms such as Salmonella or S. aureus. All of the specified microorganism tests have undergone changes. Media for enrichment, subculture and selection have changed for most microorganisms. Similar to the Microbial Enumeration Test description in harmonized USP <61>, methodologies for Absence of Specified Microorganisms are described in more detail. One significant difference in USP <62> is the prohibition of retesting, which is allowed in the current USP <61> chapter using a 25-gram sample.
Stay a Step Ahead
There’s no better time than now to prepare for changes to the USP microbiology general chapters. Here’s how:
Prepare for revalidation
Based on changes in the harmonized chapters, products may need to be revalidated. Reasons include — but are not limited to — media requirements, testing conditions and the amount of sample to be used. For example, if validation has been performed using a different type of media, this portion of the analysis may need to be revalidated. Pharmaceutical companies and their outsourcing providers should also consider the possibility of a sample that previously passed at a specified dilution not passing using the newly-specified media.
Plan ahead – for material, cost and time
Other considerations are the additional amount of material that will need to be consumed in the validation process, as well as the cost associated with performing this analysis. Time should also be considered. Should the analysis not meet the requirements initially, additional dilutions may be necessary, which will require additional time.
Account for changes to sample amounts
Depending on the test or combination of tests, the sample amounts that will be required may vary. As per harmonized USP <61> in the section covering testing of products, the amount used for the test should be 10g or 10mL. For fluids or solids in aerosol form, it is necessary to test 10 containers. For transdermal patches, 10 patches are to be tested. Additional information to justify using less product is provided in the harmonized chapters; examples include small dosage units, small batch sizes or limited number of articles in a batch. Because of changes in sample amounts described in the harmonized chapters, we recommend that the minimum amount of product submitted to your analytical services partner for revalidation in conjunction with routine analysis be 20g or 20 mL. If the sample does not pass revalidation then additional sample will be required.
Work with a partner who is willing to work with you
Your contract testing laboratory is an extension of your own internal testing laboratory. Therefore in order to best assist you in this transition, choose a partner who has considered the impact of these USP chapter changes and is planning ahead. For example, you might choose to align your organization with a contractor who is offering both validation services and routine analysis now, in the early phases, to ensure that the testing will be in compliance with the harmonized chapters that will become effective in May 2009. Find a full-service quality control testing laboratory with the expertise and equipment to perform a majority of the testing requirements defined in the USP. Their staff should be committed to staying abreast of changes in the USP so that customers can be confident that its services are performed according to current pharmacopeial requirements.
Changes to USP chapters are inevitable, but there are steps you can take now to ensure that you and your contract partners are compliant with USP Chapter <467> and in sync with anticipated USP <61> and USP <62> chapters. The closer you work with your outsourcing alliances, the more equipped you’ll be to handle the latest testing and validation requirements – and minimize the costs, materials and time associated with these changes.