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Frequently Asked Questions About the USP Verified Drug Substance Verification Program
What are the steps involved in obtaining USP verification? After a customer has spoken with our Product Team and decided to enroll an API or excipient:
At each step, USP will notify the Participant of any observations or deficiencies that may preclude successful completion of the Program. The Program is a partnership where both USP and the Participant must follow time lines and specified steps. The most efficient verification occurs when these timelines are optimized. What is acceptance criteria? The ICH Q6A guideline Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances defines "Specification" as a list of tests, reference to analytical procedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described. "Conformance to specification" means that the drug substance or drug product when tested according to the listed analytical procedures will meet the listed acceptance criteria. How can we apply for the qualification and verification program? Contact V. Srini Srinivasan, USP Vice President, Verification Programs, at or by telephone at +1-301-816-8334. Is your audit a substitute for a regulatory audit? The USP audit is not a substitute for a regulatory audit, but it will prepare a Participant for the strictest of regulatory audits. USP hires world-class professional auditors, all of whom have many years of experience, to help ensure that your organization can meet the challenges of the most rigorous regulatory scrutiny. Why will we still have an FDA audit? An ANDA filing with the USFDA may be facilitated for an ingredient that has successfully completed all of the requirements of the PIVP and that has "USP Verified" on the label. The rationale for this is the fact that we will have audited the site using the same guideline that FDA will use and we will have reviewed the same chemistry, manufacturing, and control data that will be submitted to FDA for FDA's review. Since we will have examined many of the same issues as the FDA will examine, the FDA audit should find few deficiencies (there will always be some because the auditor is a different person) and the document review by FDA should be easier as we will have identified any major problem areas during our review. However, there will still be an FDA audit and review. If my site is ISO certified, does this automatically lead to USP Verification? ISO certification does not automatically lead to USP verification. There are many differences between the ISO certification and USP Pharmaceutical Ingredient Verification Program. USP verifies ingredient manufacturing practices that are specific to the site where the ingredient is manufactured, whereas ISO certifies the Company's overall processes. Also, ISO does not deal with individual products/ingredients, or with manufacturing practices that are specific to ingredients and the site. My company is frequently audited already. Why should we invite USP to audit us? USP's audit is a mandatory component of a comprehensive verification program. The program goes far beyond just an audit to also include 1) document review, 2) laboratory testing and 3) post-verification monitoring and surveillance. USP's comprehensive approach assures our customers that we are thoroughly and objectively verifying the quality of their ingredients and processes, not just one or the other. On the audit itself, the USP audits for drug substances and excipients are meant to be the most rigorous and independent of audits based upon ICH Q7 Guideline — Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients and the IPEC/PQG Guide for Pharmaceutical Excipients. What guidance is used to determine cGMP? The ICH Q7 Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients is used for drug substances while the IPEC/PQG Guide for Pharmaceutical Excipients is used for excipients. What is the time cycle for these audits? Is the audit a surprise? USP will visit a site for approximately 3-5 days for the first year's audit with 3 days being the target. The Participant will have already prepared for it, by completing pre-audit steps with USP. A Participant will have the opportunity to submit several timeframes during which the Participant will be manufacturing the ingredient and USP can visit. USP will inform the Participant of the general timing for the audit and offer an agenda. However, in certain situations, if USP has reason to be concerned about a situation or event at the Participant's manufacturing facility, USP reserves the right to conduct an unannounced audit at its sole discretion. Will USP Verification replace the DMF? No, the DMF-type of information is a critical portion of the document review associated with the verification program. Will USP Auditors help train and improve the skills of my staff to advance the quality of our internal audits? Our auditors will offer observations that the audited company should be able to use in order to improve manufacturing quality. Training the Participants' staff is beyond the scope of this program. How can I tell my customers what USP Verification means to them? The USP verification assures that the consistency of quality in process (good manufacturing practice) and product has been verified by an independent, ethical, and credible third party - USP; and that USP has issued a Certificate of Standards Compliance. How does USP protect customer data? USP protects customer data with the utmost confidentiality. We are bound by United States law in the License Agreement that we sign with each client to do so, further, USP has nearly 200 years of independent experience in handling and protecting the confidentiality of customer data through their submissions of information that are used for standards development. Would USP report an adverse situation to a regulatory body? If an imminently threatening deficiency were exposed regarding an ingredient that is used in an approved product, USP would work with the Participant's management to report these deficiencies to the appropriate regulatory authority in the interest of the public health. If management chose not to comply, and as stated in our Programs Manual for Participants How does USP determine the fee structure for Verification? The fee structure is based on the anticipated and actual costs associated with review of manufacturing and quality control documents, laboratory testing, and performance of the GMP audit. How is the fee paid to USP? The fee is payable at the time the License Agreement is signed and work commences. The fee will be placed in an account designated only for the Participant and charges will be debited against it. The Participant will receive a monthly statement of account. What is the re-verification process and what does it cost? The life cycle of the License Agreement is for three years. Re-verification follows the exact process as the initial verification and a well-prepared company, following best practices may expect to move through re-verification with ease. Will the GMP audit be ingredient specific or manufacturing site specific or ingredient cluster specific? Does this affect my pricing? GMP audits are normally ingredient specific, however, if a parent ingredient is verified, derivative ingredients (e.g.; esters, salts,) may be covered without an additional GMP audit, as long as the derivative ingredient was manufactured using similar equipment and on the same site. These derivative ingredients are subject to the same performance standards and testing as the parent ingredient. If other ingredients are manufactured at the same site, it may be possible to perform an extended audit and cover all of these ingredients at the same time which may reduce the cost of the audit. What is the remedy structure of the USP Audit when a deficiency is identified? Deficiencies noted during the audit will be described in writing in the form of a report and grouped by their severity. Manufacturers are required to address each deficiency with the goal of full compliance to the ICH Q7 Guidance. All deficiencies must all be fully addressed before the verification process may move to the next program step. Details on types of deficiencies can be viewed in our Participants Manual Who are USP auditors? USP auditors are highly competent professionals with years of second- and third-party auditing experience, as well as rigorous training with USP. USP uses our own staff as auditors and, when necessary, complements that staff with carefully selected contract auditors who serve as highly experienced independent consultants to USP. Our contracted auditors serve USP under the same rules of confidentiality as our employed staff. If your auditor travels to my company and finds it is not prepared for an audit, what happens? USP will make every effort to insure the Participant is prepared for the cost and activities related to an audit before it is scheduled. This is supported by the requirement for pre-audit documentation which provides our staff the opportunity to assess the level of preparedness and enables the Participant to understand whether they are ready for an audit. If the USP staff believes that the Participant is prepared for an audit, the USP staff will coordinate a time convenient to both parties. If the Participant is unprepared, USP will not come for the audit and will provide feedback to the Participant regarding the deficiencies that need to be addressed. If my company has manufacturing sites in a third country, how will that be addressed? USP is prepared to have their auditors travel to the location(s) where a Participant's manufacturing site is or are located, recognizing that actual travel expenses are billed separately from the Verification Fee. If my company purchases small quantities of ingredients from another company that purchases the bulk amount, how will that be handled? If a Participant is purchasing small amounts of ingredients from another company the additional company might have to be audited as part of the process. Factors that play into this decision include review of the participant's vendor qualification program and the nature and intended use of the ingredient purchased. If my company makes different grades (food, cosmetic, drug) of the same ingredient, how will this affect the audit process? The USP Verification Programs cover a broad range of ingredients used in human health care such as drug substances, dietary ingredients used in dietary supplements, and excipients. These Programs differ from each other in respect to the Good Manufacturing Process (GMP). Who will collect the samples for surveillance studies? USP may request that the Participant's representative ship the identified samples to USP's laboratory. Alternatively the USP auditor, when on site for audits, may pick up randomly selected samples of the ingredient(s) from the lots identified by USP for testing during the post-verification period documentation review or during the GMP audit as necessitated by circumstances. What is the time between signing the License Agreement and completion of the verification process? A highly prepared participant can expect to receive the Certificate of Standards Compliance within 6-8 months after the License Agreement is signed. What is the procedure for getting another ingredient verified after a time lapse of, for example, 6 months since the initial ingredient's verification? If the new ingredient is manufactured using similar procedures as the first one with similar equipment at the same site a second audit may not be necessary. At the time of the next regular audit, both ingredients will be considered. However, document review and analytical testing will be required. Will food and drug regulators from my country recognize the USP verification? USP is meeting with selected regulatory agencies worldwide to help them understand the value that USP verification brings to improving drug quality. Each regulatory agency will determine what recognition to give USP verification. Does USP partner or collaborate with EDQM? USP is interested in partnering with EDQM but has not yet reached an agreement. The competent authorities in the European Union will accept third party audits; it is incumbent upon the Participant to work with authorities for acceptance of third party reviews. How does the program help to market products in Europe and elsewhere? The competent authorities of the European Union will be accepting third party audits as part of the review of marketing applications. The audit performed by USP should be accepted under these conditions. USP-NF monographs are recognized and accepted by many regulatory authorities in countries around the world. If specifications are different from the USP-NF monograph, what is the course of action by USP? Where there is no USP-NF monograph, then USP will use the specification submitted by the Participant for the laboratory testing. Part of this testing will include a determination of the adequacy of the specification. Upon successful completion of the Pharmaceutical Ingredient Verification Program, the participant may be asked for permission to use the submitted information in developing a draft monograph that will be published in Pharmaceutical Forum for public comment and eventual inclusion into the compendia. |
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