美国和欧洲观点：制药行业中周期性检测或跳检

beiwei5du

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.

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.

USFDA Prospective [8]

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

EMEA_ICH topic Q6A       specifications: Test Procedures and Acceptance Criteria for New Drug       Substances and New Drug Products: Chemical Substances.           ICH q6a Guideline       Specifications: Test procedures and Acceptance criteria for New Drug       Substances and New Drug Products. Comments for its application.           The       Complete Stability Testing for a Successful Application Based on a       (Strategies, Requirements, Basic Principles Performance, Documents)2. Basic principles of       stability testing.           Joint position paper from       excipient manufacturers, drug product manufacturers and USP on       pharmaceutical excipient testing and control strategies; Based on a PQRI       survey and workshop.           Specifications and Control       Tests on the Finished Product.           Lyon       RC, Taylor JS, Porter DA, Prasanna HR, Hussain AS (2006)Stability Profiles of Drug Products Extended beyond       labeled Expiration Dates. J Pharm Sci 95: 1549-1560.           USFDA       Guidelines (2004)Changes to an Approved NDA or       ANDA; Specifications-Use of Enforcement Discretion for Compendial       Changes.           IRISH       Medicines Board (2009)Quality Assessment and GMP       Similarities and Differences, EMEA.           EDQM: Topic 7_Certificate of Pharmaceutical       Substances.

beiwei5du

上面的文章总是感觉有很多矛盾之处，下文选自的是：NOTE FOR GUIDANCE SPECIFICATIONS: TEST PROCEDURES AND ACCEPTANCE CRITERIA FOR NEW DRUG SUBSTANCES （活性成分，一般指API）AND NEW DRUG PRODUCTS（制剂）: CHEMICAL SUBSTANCES (CPMP/ICH/367/96)（2000年5月实施的，不知道现在是否有效，请教一下在哪里查询相关法规的有效性呢？？？谢谢！！@一沙一叶 @uniofer ）
2.1. Periodic or skip testing
Periodic or skip testing is the performance of specified tests at release on pre-selected batches and / or at predetermined intervals, rather than on a batch-to-batch basis with the understanding that those batches not being tested still must meet all acceptance criteria established for that product. This represents a less than full schedule of testing and should therefore be justified and presented to and approved by the regulatory authority prior to implementation（这个应该是针对于公司原料药和制剂，而非原辅料，包装材料？？？求指教）. This concept may be applicable to, for example, residual solvents and microbiological testing, for solid oral dosage forms（这里就提及到针对于的口服固体制剂）. It is recognized that only limited data may be available at the time of submission of an application (see section 2.5). This concept should therefore generally be implemented post-approval. （由于考虑到数据的有限性，一般是针对于批准后的变更进行periodic or skip test的实施）When tested, any failure to meet acceptance criteria established for the periodic test should be handled by proper notification of the appropriate regulatory authority(ies). If these data demonstrate a need to restore routine testing, then batch by batch release testing should be reinstated.（若后期存在periodic or skip test failure的情况应该通知相应的regulatory agency,并且在后期会提供相应的evidences以维持其periodic or skip test,如果不能这需要恢复成full test）

beiwei5du

Periodic & skip testing - 1
l“Periodicor skip testing is the performance of specified tests at release on preselectedbatches &/or at predetermined intervals, rather than on a batch-to-batchbases”
lAllbatches must nevertheless meet the full product specification if tested
lOncea manufacturer has developed confidence in the manufacturing process & anumber of consecutive batches have passed the test in question, testing may bereduced to one in every x batches, or once every x months, where x is a numberthat varies with the test in question  

lCertaintests are considered ‘critical’ in terms of GMP, & must be conducted on every batch. Examples include identification & assay of the active(s).
lRegulatoryapproval must be obtained (on a product-specific basis) before periodic testingmay be implemented
lInthe event that a batch is tested & fails to meet acceptance criteria,regulatory authorities must be immediately informed. The batch may be recalled.The reason for the failure must be identified in order to assess theconsequences for other batches.

选自WHO《Training Workshop onPharmaceutical Development with focus on Paediatric Formulations
》http://apps.who.int/prequal/trainingresources/pq_pres/workshop_China2010/english/22/001-DosageFormDesign.pdf


这样看来，如果实施相应的periodic/skip test，相应的召回风险也会更大。

阿炳1987

我只想说，有种晕车的感觉

一沙一叶

FDA官网上是否还有这个指南？国内也有一些不必全检的，制剂公司对于原料药和包材可以不必每批全检哦

xiaok1978

原料药成品都要有检验报告的，你不能提供给客户的检验报告还不一样吧？

福娃

看到楼主上述描述，有点晕

xxjiangxi

谢谢楼主分享！！！！！

beiwei5du

我个人认为，针对于注册标准的PT/ST行为可能需要像上面所说的程序，但是对于内控标准（高于注册标准，比如增加了相应的其他检测指标），针对于这些指标的PT/ST无需走上面的程序，公司内部评估即可。@hongwei2000

hongwei2000

beiwei5du 发表于 2016-9-30 11:05
我个人认为，针对于注册标准的PT/ST行为可能需要像上面所说的程序，但是对于内控标准（高于注册标准，比如 ...

当地监管当局的要求永远是第一位的
即使风险较低的要求你也必须做到
当然如果内控的要求不在监管和注册范围内的
本身就是你文件规定的东西
那么也就是按照你文件的要求来执行即可

cts9166

ji yu dui chan pin gong yi de li jie he ba wo ,wo ren wei shi ke yi tiao jian de.

小金库

谢谢共享