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Periodic or Skip Testing inPharmaceutical Industry: Us and Europe Perspective
完整的文章请看在http://www.omicsonline.org/open-access/periodic-or-skip-testing-in-pharmaceutical-industry-us-and-europe-perspective-2153-2435.1000283.php?aid=23486下载PDF version Useni Reddy Mallu1*, Raman NVVSS2, Sachin RD1 and Anand K1 | | 1 Department of Chemistry, Sri Krishnadevaraya University, Anantapur, Andhra Pradesh, India | | 2 Hetero Drugs Ltd. (RandD), Plot No. B. 80 and 81, APIE, Balanagar, Hyderabad 500018, Andhra Pradesh, India | | Corresponding Author : | Useni Reddy Mallu
Sri Krishnadevaraya University Chemistry
Anantapur, anantapur, AP 500072, India
Tel: 9490310239
E-mail: drusenireddymallu@gmail.com | | Received December 16, 2013; Accepted January 17, 2014; Published January 23, 2014 | | Citation: Mallu UR, Raman NVVSS, Sachin RD, Anand K (2014) Periodic or Skip Testing in Pharmaceutical Industry: Us and Europe Perspective. Pharm Anal Acta 5:283. doi:10.4172/2153-2435.1000283 | | Copyright: © 2014 Mallu UR, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
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Abstract Periodic Testing (PT) or Skip Testing (ST) is animportant and widely discussed concept for the purpose of cost saving in thegeneric pharmaceutical industry where widespread expenditure is a necessity. Asthere is no particular/ appropriate/apropos guideline recommending theimplementation of the PT or ST concept so pharmaceutical companies implement itdepends on their vendor qualification procedure and other aspects. Allpharmaceutical industries have their internal Standard Operating Procedure(SOP) for the implementation of periodic or skip testing. These tests can beimplemented for Active Pharmaceutical Ingredients (APIs), excipients, packingmaterials and inprocess testing of finished products analysis. Implementationof PT or ST for API, excipient and packaging material can be approachedaccording to SOPs which would be available for an audit by the regulatoryagencies. However, the implementation of PT for in-process testing of finishedproduct can be undertaken only after seeking concurrence from the agency eitherduring the review of a marketing authorization application or after approval ofthe application. A suitable supplement or variation needs to be submitted tothe agency for its review if PT is to be implemented for in-process testing(针对于API,辅料和包装材料的周期性检测和跳检可以公司内部评估并且需要的文件支持，而针对于finished product的IPC检测则必须经过官方批准后才能实施）.This article explains the periodic testing/skip testing approach for in-processsamples, APIs, excipients and packing materials. | Keywords | | Periodic testing or skip testing; SUPAC (Scale Up and Post Approval Changes); Pre-approval supplement; Variations; Filing documentation; Routine analysis | | Introduction | NPharmaceutical industry and regulatory agencies have acquired significant knowledge about drug product development by utilizing scientific approaches and automation. In the past drug product quality was ensured by testing but now a new concept is being considered which believes in building quality in the product by design. The critical quality attributes for the drug product are controlled by building a control space within a design space by implementing the scientific and statistical approaches such as Quality by Design (QbD) and Process Analytical Technology (PAT). Before the implementation of PT/ ST approaches for the testing of commercial products, the applicant should have sufficient data on the control strategy which has been built in the manufacturing process of the product to ensure product quality [1-3]. | | Periodic Testing (PT) or Skip Testing (ST) | | As per WHO, “Performance of specified tests at release on preselected batches and/or at predetermined intervals, rather than on a batch-by-batch basis, with the understanding that those batches not being tested still meet all acceptance criteria established for that product. This presents a less than full schedule of testing should therefore be justified and presented to and approved by the regulatory authority prior to implementation”. | | PT or ST frequency, criteria, stage and material on which it has to be implemented are usually defined by the company’s written procedure after taking in to consideration vendor qualification information and other available data. The frequency for the implementation of Periodic testing (PT) or Skip testing (ST) may be one batch per twenty batches or the first batch manufactured every year (whichever is earlier) and it may vary from one company to another. PT or ST can be implemented for the testing of Active Pharmaceutical Ingredients, Excipients Packaging material and in-process samples. PT/ST cannot be implemented for finished product testing.（但在另一份文件中却提及到可以适用于FPP realease testing） | | Where We Can Apply | | Periodic testing or skip testing should be implemented after performing sufficient risk evaluation and assessment of product quality during drug product development. It should be implemented at commercial level only after gaining sufficient confidence. Periodic or skip testing approach and stages are represented in the Figure 1. | | Periodic (Pt) or Skip Testing (St) Selection Considerations | | PT or ST can be selected and implemented for the testing of regular commercial batches. For selecting the periodic or skip tests, the following points should be considered, | | 1. Whether materials are received from the approved supplier. | | 2. A documented history of satisfactory results for material supplied and performance of supplier is available. | | 3. A documented history of satisfactory performance for the process and product is available. | | 4. Compliance with specific regulatory requirements of testing is ensured. | | 5. Sufficient development data for the specified tests is available. | | 6. Scientific justification can be provided. | | 7. To be implemented for tests which are not critical to assess the product quality. | | 8. Batch to batch retesting to be stored in the event of failure and it should be properly investigated and closed. | | 9. An impact assessment of the PT or ST should be undertaken. | | 10. Does the specification or method provide information about the purity or potency of the finished product? If not, the specification or method should be reconsidered. | | 11. Analytical method should predict or prevent the compliance issue. | | 12. What would be the regulatory impact of eliminating or reducing the test? | Risk assessment must be carried out for all suppliers of the material being assessed. Where there is more than one supplier for a particular material, then each supplier must be assessed individually. A periodic review must be conducted to ensure that the risk assessment and PT or ST schemes remain valid. Where an assessment has identified a significant risk it must be appropriately mitigated. | Implementation of the PT or ST concept for the important test items such as description, loss on drying, purity test and microbial testing etc.（这个是什么意思，是不是说反了？？ ） The list of recommended test items are represented in the below table for active ingredients, excipients and packing materials (Table 1).（Table 1: Mandatory test items for API, excipients and packing materials.不知道这个表的数据的references是出自哪里的） | | Periodic or Skip Testing for in-Process Samples | Skip testing approach can be implemented for in-process samples of all categories of finished drug products such as tablets, capsules, semi solids and liquids. This can be implemented after review of data for 20 to 30 consecutive batches which have been manufactured without any change in process, formula, equipment or specification. PT/ST can be implemented after approval from the respective regulatory agency. After implementation of PT or ST if the process, formula, equipment etc. is changed then the skip testing procedure should be reevaluated. If any OOS/incident is encountered due to process quality and the Root Cause Analysis indicates in-process testing or a change in the process, specification or test procedures, then complete testing needs to be performed on few consecutive batches without any change. The internal quality assurance team will be responsible to perform the risk assessment (Figure 2，针对于IPC的流程图比较详细) [4-7]. | | Periodic or Skip Testing for Api, Excipients and Packing Materials | | Generally, after analyzing 30 to 40 batches, periodic testing or skip testing may be implemented if data is found satisfactory and without much variation. If any OOS/incident is encountered then complete testing of few consecutive batches is to be performed and the quality assurance team needs to perform the risk assessment. Different companies may follow different PT or ST procedures (Figure 3). | | Regulatory Authorization | | PT or ST may be implemented for APIs, excipients and packaging material after a favorable review of sufficient batch data and by preparing SOPs which would be available for an audit by the regulatory agencies. However, for implementation of PT for in-process testing of finished product concurrence from the agency during the review of an application or after approval is necessary. A suitable supplement or variation needs to be submitted to the regulatory agency for its review if PT is to be implemented for in-process testing of finished product post approval. | | | | As per the USFDA recommendations, PT or ST implementation has to be submitted as a supplement to an approved application,. Some changes may not require approval before implementation and some changes may require an approval before implementation. Figure 4 represents the PT or ST items classification as per the USFDA. | | Major-Prior Approval Supplement (PAS) | | PAS submission is required for implementation of PT or ST for in-process testing of the finished product. We cannot implement PT or ST for in-process testing of the drug product unless agency approves the supplement. | | Moderate-Changes Being Effected 30 Days (CBE-30) | | Relaxing an acceptance criterion or deleting a test for raw materials（原辅料） used in the manufacture of the drug substance（活性成分，一般指API）, in-process materials prior to the final intermediate（中间体前的过程物料）, starting materials introduced prior to the final drug substance intermediate（最终活性成分中间体前引入的starting material）, or drug substance intermediates (excluding final intermediate)(活性成分中间体，最终中间体除外） Relaxing an acceptance criterion or deleting a test to comply with an official compendium that is consistent with FDA statutory and regulatory requirements. | | CBE 30 days | | The CBE (Changes being effected) 30 supplement serves as a notification to the FDA that a change will be implemented in the process, analytical techniques/technologies. The Agency has 30 days from the day of receipt to respond to the applicant. This is usually a minor change which does not impact final product quality. The FDA has 30 days to respond as to whether the changes are satisfactory. If the manufacturer does not receive any response within the 30-day period, it may be assumed that the change is acceptable. | | Minor (Annual Report) | | For DS/DP(DP是指什么？？？）, the addition or revision of an alternative analytical procedure that provides the same or increased assurance of the quality being tested as the analytical procedure described in the approved product or deletion of an alternative analytical procedure. | | Annual report: For the above change, applicant should provide the sufficient data in the annual report. | EU Variations (Type-IA) [9] | | Implementation of PT or ST is categorized as a type-IA variation and the applicant can proceed with annual report submission. As per EMA recommendations, Type IA variations do not require approval by the authorities before their implementation by the holder. However, within 12 months from the date of implementation, the holder must submit simultaneously to all national competent authorities. It needs to be highlighted that if the variation is to be rejected by the competent authority then the holder would immediately stop to implement the concerned variations. Figure 4 （figure 4到底是根据USFDA制定，还是根据EMA制定的呢？？）represents the PT or ST implementation as per the EMA regulations. | | The specification parameter does not concern a critical parameter, for example any of the following: assay, impurities (unless a particular solvent is definitely not used in the manufacture of the active substance), any critical physical characteristics e.g. particle size, bulk or tapped density, identity test, water, any request for skip testing.（到底讲的什么意思呢？？？） | The specification parameter or proposal for the specific dosage form does not concern a critical parameter for example: assay, impurities (unless a particular solvent is definitely not used in the manufacture of the finished product) any critical physical characteristics (hardness or friability for uncoated tablets, dimensions…) a test that is required for the particular dosage form in accordance with the general notices of the Ph. Eur.; any request for skip testing.（到底讲的什么意思呢？？？） | | Conclusion | Periodic Testing or Skip Testing can be implemented for testing of products which are intended for commercialization. Generally, the industry has to assess the possibility of acceptance of the parameters by the regulatory agency. Generally parameters are proposed for PT or ST for a minimum of 20 and 30 lots/batches of packaging material and excipient etc. If the change is accepted by the agency then the company should follow the internal SOP on PT/ST for the implementation of PT/ ST. As per USFDA, these changes are addressed under PAS, CBE-30 or annual reportable category..As per EMA, these changes come under type-IA (annual reporting) variation. As per USFDA, if the change is major then the applicant should submit the prior approval supplement, if the change is moderate then the applicant should follow the CBE 30days procedure and if the change is minor then the applicant can include the change in the annual report. If the variation is accepted then PT/ST may be implemented. But if the variation is rejected by the agency then the sponsor should immediately stop the implementation. | | References | | |
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