Introduction of PIC/S Accession Procedure and Suggestions forEstablishing a Unified Quality Management System in China

Hu Shigao,Wu Zhiang

(1.School of Business Administration,Shenyang Pharmaceutical University,Shenyang 110016,China;2.Anhui Center for Drug Evaluation and Inspection,Hefei 230051,China;3.Yeehong Business School,Shenyang Pharmaceutical University,Beijing 10055,China)

Abstract Objective To introduce the accession procedure and evaluation of PIC/S,and help relevant departments in China to understand the requirements of PIC/S in detail,and to promote the process of China’s entry into PIC/S.Methods The procedures and steps of joining PIC/S,the evaluation process of PIC/S,and the experience of several countries in joining PIC/S were introduced and analyzed,which could help the relevant personnel in China understand the specific contents.Results and Conclusion According to the requirements of PIC/S,it is necessary to establish a unified GMP quality management system.

Keywords: PIC/S;GMP;accession procedure;quality management system

In September 2021,China’s NMPA officially started the application for PIC/S membership,which is a good opportunity for China to actively participate in international rulemaking and improve the influence of China’s drug regulatory and pharmaceutical industry in the international community.After years of development and reform,China’s drug inspection has formed a relatively perfect legal and regulatory system and inspection process.Therefore,being familiar with the PIC/S requirements is of great importance for the reform of GMP management system.

1 Introduction to the PIC/S

PIC/S used to be Pharmaceutical Inspection Convention (PIC),which was established in 1970 by 18 countries of the European Free Trade Association for the purpose of breaking down barriers to drug trade between countries and promoting the unification of GMP.Therefore,it has the nature of a national alliance[1].In November 1995,in order to strengthen cooperation with non-EU Member States and break the restriction that PIC is limited by the EU legal system and cannot include more participants,PIC further established the cooperation plan of non-state formal agreements composed of drug inspection agencies of various countries or regions,the PIC Scheme,which is short for PIC/S[2].PIC/S was registered in Geneva,Switzerland in 2004 under the“Swiss Civil Code” (Article 60ff),which is similar in legal status to the International Committee of the Red Cross (ICRC).But unlike the United Nations,PIC/S is not an association of treaty-based international organizations.

2 Purpose and membership requirements of PIC/S

The PIC/S aims at establishing a framework for drug inspection information and experience sharing on a voluntary basis,coordinating the training of inspectors and technical experts in relevant fields,strengthening the constructive exchange and cooperation of participating institutions in the field of drug inspection,maintaining mutual trust,improving the quality of inspection,developing and maintaining coordinated drug GMP standards,and promoting the coordination and unification of inspection standards and procedures of drug regulatory agencies all over the world.

Based on the above purposes,PIC/S requires the participating inspection institutions to possess an inspection system equivalent to PIC/S,and the requirements and procedures within the framework of the inspection system can ensure the effective implementation of PIC/S objectives,which is conducive to the operation of PIC/S and the cooperation among member institutions.The inspection agency’s actions shall comply with the requirements of the quality management system designed to ensure that the necessary standards are maintained.In addition,inspectors of participating institutions are required to have qualifications and experience related to their work.

3 PIC/S accession procedure

PIC/S pursues the harmonization and unification of GMP among various countries and regions.However,since the national conditions of all countries are not completely consistent,PIC/S does not require the GMP regulations and inspection systems of all countries or regions to be completely consistent due to the consideration of practical factors.To achieve the implementation effect based on the difference of member states,they should promote and harmonize GMP standards and guidance documents recommended by the PIC/S.Therefore,to improve the efficiency of assessing the work of national or regional applicants,the application process includes two steps:“pre-accession application” and “formal accession application”.

3.1 Evaluation indicator tool

For the indicator tool to evaluate applicant institutions,PIC/S selects the audit checklist developed by the EU-Canada GMP Mutual Recognition Agreements (MRAs).This list was developed in 1998 in support of the European Economic Area Joint Audit Programme (EEA-JAP) and the Mutual Recognition Agreement (MRA) assessment program with Health Canada to assess Health Canada and all EU drug inspection agencies.

In some EU countries,there are several GMP inspectorate.In Germany,for example,there are 16 provincial drug inspection agencies like China and a comprehensive coordination center for drug inspection.In some countries such as the UK and France,there are independent inspection bodies for medicines for human and veterinary use.In 1998,Canadian auditors of Health Canada developed this tool for the purpose of signing a GMP mutual recognition agreement with the European Union and conducted a complete assessment by visiting approximately 50 GMP inspection agencies in 15 EU member countries.This audit was completed in 2002 and the EU-Canada bilateral GMP mutual recognition agreement entered into force.

In 2004,10 new member states joined the EU,and the audit process was restarted to ensure the effectiveness of the MRA.Health Canada assessed these 10 countries based on this audit checklist.PIC/S revised and updated the audit list together with EMA and Health Canada in 2005 and 2012 respectively.The current version is 2012 (PS/W1/2005).PIC/S applies it to the assessment process of PIC/S preaccession application,formal application,and Joint Reassessment Programme (JRP) after accession.The scope of assessment includes drugs,APIs,test drugs,and intermediates[3].

3.2 Phase of pre-accession application

According to the PIC/S,the pre-accession application is voluntary and helps applicants to better understand the PIC/S requirements before the formal application,which identifies and bridges the gaps between the existing GMP and the PIC/S GMP.

PIC/S recommends that applicants meet one of the following criteria for voluntary pre-accession application.

(1) The applicant institution does not adopt PIC/S GMP guidelines.

(2) The applicant institution does not regularly participate in PIC/S training activities.

(3) The applicant is not sure whether it meets PIC/S requirements.

(4) The same quality management system has not been introduced in the institution according to the PIC/S recommendation (PI 002).

The applicant should first complete the selfassessment questionnaire (PS/W 1/2011),audit list(PS/W 1/2005) and the list of relevant supporting documents,and then it should submit the English electronic version to the PIC/S Secretariat in the form of email attachment or CD-ROM.The PIC/S Secretariat will submit the relevant information to the PIC/S Committee.The pre-accession application period shall not exceed 2 years from the time the PIC/S Secretariat formally notifies the applicant institution of receipt of the pre-accession application materials.When the process of pre-application evaluation begins,PIC/S Committee will comprehensively consider the situation of the applicant,appoint one PIC/S Committee member as rapporteur and one or two co-rapporteurs (as the case may be) to form an audit team to evaluate the laws and regulations,inspection mechanism and quality system of the applicant in the form of document review.Only when the rapporteur considers it necessary,he will visit the applicant institution for short-term on-site assessment,so as to put forward a gap analysis that is more suitable for the actual situation of the applicant institution[4].Generally,in the evaluation of preaccession applications,the rapporteur only assesses whether the applicant institutions have fully and correctly understood the questions and indicators in the questionnaires and audit lists.

When the pre-accession application is completed,the audit team will complete the gap report of the applicant,and the PIC/S Committee will give suggestions to the applicant accordingly.And then,the applicant can decide to apply for formal joining or make corresponding improvement and correction as appropriate.The pre-accession application institution does not need to pay the application fee and annual membership fee,but the pre-accession application institution can pay half of the annual fee on a voluntary basis as the registration fee for participating in various PIC/S conferences and obtaining corresponding conference materials,including nonpublic technical guidelines and draft guidelines.If the rapporteur considers it necessary to conduct an on-site assessment to complete the gap analysis,the applicant shall bear the travel expenses of relevant personnel.

3.3 Phase of formal accession application

3.3.1 Application process

Institutions intending to submit an application for formal accession shall express their willingness to join the PIC/S Secretariat in advance,fill in the evaluation questionnaire (PS/W1/2011),audit checklist (PS/W1/2005) and all relevant supporting documents,and submit the English electronic version to the PIC/S Secretariat in the form of email attachment or CD-ROM.After receiving the application,PIC/S Secretariat will review the integrity of the information and take this as a sign to start the 6-year formal application timing.If the audit result is in conformity,the PIC/S Secretariat will notify the applicant to pay the application fee and report it to PIC/S Committee to form an audit team,including one rapporteur and at least one co-rapporteur,to carry out follow-up evaluation.If the audit result is unqualified,the application institution will receive the returned materials and fill them in again.

After completing the document review and on-site evaluation,the PIC/S Committee will make a decision on whether to agree to the application institution’s participation according to the comprehensive study and judgment of the evaluation report submitted by the rapporteur.If the application is not approved,the applicant will be notified for further observation.Theoretically,it can become a full member of PIC/S as soon as 1.5 years after the application is submitted.However,according to the accession experience of some countries in the world,most application institutions need 3-5 years to formally join the PIC/S.If the applicant fails to join within the 6-year time limit,the application shall be invalidated,and the applicant should resubmit the application.However,within the 6-year period,PIC/S allows the applicant institution to stop counting for no more than 1 year.The reasons for stopping counting include the updating of national laws and regulations,institutional reform and reorganization,etc.

After the applicant becoming a member of PIC/S,to ensure the stable inspection quality of PIC/S member organizations,the drug GMP inspection organizations of all formal members must regularly reevaluate and inspect the quality management system according to the joint re-evaluation plan of PIC/S[5].

Unlike the pre-accession application,PIC/S requires the formal applicant to send representatives to participate in the annual PIC/S Committee,seminars,and other training activities (such as expert group seminars or joint visit plans).Besides,they should pay the fees for supporting the above activities and the annual fees for formal members in a timely manner as required by PIC/S.

3.3.2 Evaluation process

The PIC/S rapporteur shall complete the following tasks with the assistance of the corapporteurs.

(1) To ensure that the application materials are completed.

(2) If the pre-accession application has not been carried out,the application materials shall be quickly estimated first to ensure that the applicant meets the basic requirements of PIC/S.If the rapporteur believes that there is a certain gap,it is suggested that the applicant institution should carry out the pre-accession application procedure first.

(3) To evaluate the contents of the application materials,submit the periodic report to the PIC/S Secretariat at least 30 days before the latest committee meeting,and timely notify the chairman of the compliance sub-committee of the dynamic information.

(4) To organize discussions during the hearing of the representative of the applicant and lead the PIC/S audit team as the group leader to conduct on-site assessment on the applicant.

(5) To develop a final assessment report that includes the committee’s comments on the need for action.

In the formal application,in addition to document review,the applicant shall invite the audit team of PIC/S Committee to the country where the applicant is located to conduct on-site assessment on the contents of the audit list such as the inspection system,inspection mechanism,inspection methods and procedures.It also includes the on-site assessment of the inspection organization,the on-site assessment of the inspection and testing organization and the onsite assessment of the inspection.

The duration of on-site assessment is usually about one week.First,a kick-off meeting will be held,and the head of the applicant institution and the head of the drug inspection department will introduce the GMP inspection system of the country.After the onsite evaluation,the PIC/S audit team will evaluate the quality management system,standard operating procedures (SOPs) and relevant laws and regulations of the review and inspection institution.In addition,they should understand the production license management of the drug inspection institution,the relationship with the drug review,inspection,audit and other departments,the training of inspectors,the inspection strategy and the formulation of inspection scheme.After that,PIC/S audit team will observe and evaluate the inspection sites of sterile drugs,non-sterile drugs,traditional Chinese medicine,or other types of drug manufacturers,and complete the on-site evaluation of inspection and testing institutions respectively.Finally,the audit team should summarize the results during the on-site evaluation and hold the final meeting.As for the on-site inspection evaluation,PIC/S audit team will select several local representative pharmaceutical enterprises to observe the GMP inspection of the inspection team of the applicant institution during the on-site inspection,to comprehensively evaluate the inspection procedures,inspection capabilities and the operation of relevant mechanisms.However,it should be noted that PIC/S audit team will not inspect pharmaceutical enterprises in the country or region where the applicant is located[6].

The final completion time of on-site assessment depends on the degree of compliance of the inspection mechanism,quality management system,and GMP regulations of the applicant with PIC/S requirements.Sometimes it can be as long as several years.

4 Situation and experience of some member states accession to PIC/S

Australia,the United States,Malaysia,and Singapore from the members of PIC/S are selected to learn about their accession to PIC/S,as shown in Fig.1.From Fig.1,we can learn about the time taken by the drug regulatory agencies of these countries to join PIC/S,the number of applications and the main problems[7].

5 Suggestions on establishing a unified quality management system in China

5.1 Establishing a coordinated and unified quality management system

In terms of the establishment of drug regulatory and inspection institutions of the applicant institutions,PIC/S can accept vertical management or localized management mode based on the consistency of inspection standards of GMP drug inspection institutions,such as the vertical management mode of “central+five regional offices” of the FDA of the United States[8]or the localization management mode of the federal administration of medical products and medical devices (zentralstelle der L?nder für gesundheitsschutz,ZLG) established in Germany to coordinate the management of the central and local state-level drug regulatory agencies.However,no matter what the organization setting mode is selected,PIC/S requires that drug inspection institutions at all levels should establish a highly unified quality management system with reference to international standards.

The national drug regulatory department shall conduct a survey on the construction of the quality management system of the inspection institutions of all provincial drug regulatory departments,conduct a comprehensive evaluation of the institutions that have established the quality management system,and make a unified planning and guidance on the process,strategy,and work objectives of the unified quality system.NMPA shall establish a quality system monitoring department to comprehensively guide and evaluate the quality system of provincial inspection institutions and supervise their operation.Under the condition of establishing a national unified quality management system,NMPA should undertake the work of promoting the consistency of the quality system from the bottom up,actively carry out quality system training for provincial drug inspection institutions,and promote the unified development of the quality management system of drug inspection institutions at all levels in China.

5.2 Improving the construction of various elements of the quality management system

5.2.1 Establishing a good document control system

The document control system refers to the system used by the inspection institution to control internal documents and work records.The drug inspection institution shall establish and maintain a control system for recording all documents related to the inspection system.

The inspection organization shall assign a special person or department to be responsible for the operation,maintenance,and management of the document control system.The responsible person should maintain records and update the version in the control system before the release of documents.Relevant records of quality documents,policy documents,internal SOPs,various work procedures,requirements and work templates shall be incorporated into the document control system for good preservation.The abolished laws and regulations or guidelines,the changed version of SOP or work procedure template and other documents shall be systematically updated in a timely manner to avoid the contradiction between the old and new versions of various documents and quality defects.Document changes shall be truthfully recorded in the system.

5.2.2 Preparing and maintaining the general quality management manual

The quality manual is the a summary document of the organization’s quality management system,which is to ensure the organization to perform its duties well.Drug regulatory and inspection institutions at all levels shall prepare and maintain quality manuals,including all GMP inspection related work.Organizations at all levels can determine the format and style of their quality manual according to work division,internal organization setting,personnel,resources,and other factors.However,the quality manual must include all contents of the quality system within the organization,such as the work operation of the organization and the arrangements for maintaining the quality system.The establishment of the quality manual shall be consistent with the quality system in terms of contents by referring to the standards of the international organization.

5.2.3 Completing the annual quality system audit

The audit of the quality management system can ensure the good implementation of the quality management system.It is suggested that national drug inspection institutions should take the lead in establishing national unified SOP for internal annual audit of institutional quality system and introduce relevant management measures for internal audit.Besides,it should specify the executor and the time of audit and standardize the formulation of plan,the scope of audit content,the improvement of audit results,and the retention of audit records.The annual audit contents,results and improvement measures shall be disclosed for local reference.For instance,the document template is required to include in the document control system,the integrity of the inspection records should be checked.In addition,the inspection report should make a conclusion and the technical joint review meeting must be included in the system.Finally,the defect classification of the results should be checked.

In addition,it is possible to establish an annual audit mechanism and an audit result evaluation mechanism for national drug inspection institutions to conduct local audits and interactive audits among provincial level institutions.Drug inspection institutions with poor quality system audit results should be warned,requiring them to strictly fulfill responsibilities,which can promote the quality management system.