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Draft Report – PQ-VCP Inspections Oct 2016

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Proposal for a WHO Pre-Qualification Inspection

Quality Standard and Site Inspection Process (Pre

and Post Marketing) for Vector Control Products


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CONTENTS GLOSSARY

1. Overview – purpose and need for Report 2. Approach used in developing PQ (VCP) inspection process 3. Review of existing PQ Inspection Processes 4. Introduction to Vector Control Products (VCP’s) 5. Review of VCP regulatory requirements for inspections/production processes 6. Proposal for the Quality Standard to be used for VCP’s (actives and

formulations) 7. Proposal for PQ Inspection Process for VCP’s (actives and formulations) 8. Next steps in consultation process

Appendices A Key WHO-PQ website reference guidelines B Key VCP formulation types with WHOPES listed recommendation C GMP, Principle Audit Requirement sections D ISO 9001 Standard – Key Requirements – Summary E Principles of Pre-Qualification (PQ) Process


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GLOSSARY OF TERMS Definitions

ASTM ASTM International. An international standards organization that develops and publishes voluntary consensus technical standards for a wide range of materials, products, systems, and services

CAPA Corrective And Preventative Action

CIPAC Collaborative International Pesticides Analytical Council

CRO Contract Research Organization

Dx Diagnostics

FAO Food and Agricultural Organisation of the United Nations

GCP Good Clinical Practice

GLP Good Laboratory Practice

GMP Good Manufacturing Practice

I2I Innovation to Impact project

IRS Indoor Residual Spray

ISO International Organisation for Standardisation

IVCC Innovative Vector Control Consortium

IVD Invitro diagnostics

JMPS Joint Meeting on Product Specifications

LLIN Long-lasting insecticidal nets

LN Formulation code for nets and netting

M/F Manufacture

NTD

Neglected Tropical Diseases, also Department of NTD

NOC Notice of Concern

NRA National regulatory authority

VCAI Vector Control Active Ingredient

PIC/S Pharmaceutical Inspection Co-operation Scheme

Pesticide Substance, mixture or microorganisms intended for repelling, destroying or controlling any pest, including vectors of human or animal diseases

PQP

Prequalification Programme

PQT

Prequalification team

PQ VCPAG Prequalification, Vector Control Product Assessment Group

Rx Medicines

Quality assurance

All matters that individually or collectively influence the quality of a product. It is the totality of the arrangements made with the object of ensuring that products are of the quality required for their intended use.

Quality control Pre- and post-shipment testing of quality of a product to determine compliance with specifications

QMS Quality Management System

SMF

Site Master File


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SOP

Standard Operating Procedure

SRA Stringent Regulatory Authority

VC Vector control

VCAG Vector Control Advisory Group

VCP

Vector control product

WHOPES

WHO Pesticide Evaluation Scheme

WHOPAR WHO Public Assessment Report

WHOPIR WHO Public Inspection Report


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1. Overview – Purpose and need for report

Since 1960, the WHO Pesticide Evaluation Scheme (WHOPES) has served as the primary global mechanism for establishing quality standards for, and assessing the efficacy and safety of, pesticides for use in public health. This Scheme is currently housed within the unit of Vector Ecology and Management (VEM) in the Department of Control of Neglected Tropical Diseases (NTD). International stakeholders, including industry, procurers, and WHO Member States have expressed the need for transformation within the WHO in order to have vector control evaluation processes similar to those of the other product streams (in vitro diagnostics (IVDs), medicines and vaccines) dealt with by the Prequalification Team (PQT). Alignment with existing product review streams in PQT would increase transparency in evaluation timelines and criteria, enhance quality assurance management throughout a product’s life cycle, and facilitate proactive engagement with national regulatory authorities (NRAs). This report details a proposal for a Pre-Qualification Inspection Quality Standard and Inspection Process for Vector Control Products (VCP). The report focuses on submissions for new products (including new active ingredients, new VCP formulations and generic products) and on inspection of facilities for manufacturing these materials. The vector control products considered includes insecticidal bed nets, indoor residual sprays (IRS), space sprays and larvicides and other vector control tools from established paradigms including non-chemical based products. Wherever feasible and appropriate, the proposed process is based on existing inspections used by other WHO-PQ teams for medicines, vaccines, and diagnostics. The report does not cover the inspection of CRO field or laboratory facilities where VCP efficacy trials are conducted. An additional report is being prepared which will focus on defining a risk assessment protocol for governing frequency and site selection, of post marketing inspections and product sampling and quality testing programs.


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2. Approach used in developing PQ (VCP) inspection process

The approach used to develop this proposal for a PQ (VCP) inspection process is summarised below: -

A review of existing PQT inspection processes – medicines, vaccines, diagnostics Initiation of Inspections Pre-Inspection Dossier review and establishing Inspection team International Partners collaborating on Manufacturing Inspections Factory Pre-marketing inspection by PQ Team and Quality Standards used Inspection reports and follow up actions Post-marketing inspection

An Introduction to Vector Control Products (VCP’s) A review of VCP regulatory requirements relating to manufacture and inspection

Comparison of VCP and Medicine requirements Vector Control Active Ingredients (VCAI) Pesticide Formulations used as VCP’s including (LLIN’s) and Chemical and non-

Chemical formulations (all types). Proposal for a Quality Standard to be used for VCP’s (VCAI’s and formulations) Proposal for PQ Inspection Process for VCP’s (VCAI’s and formulations)

Pre-approval inspections Post-PQ listing activities


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3. Review of existing PQ Inspection Processes

Existing inspection processes (medicines, vaccines, and diagnostics) draw on accepted procedures and approval and inspection procedures. The level of infrastructure available to support these procedures varies throughout the WHO Member states/regions. The detailed process and supporting documentation on PQ and inspection processes are available from the WHO-PQ website. Appendix A lists all the key documents on WHO-PQ website that relate to Inspections, and that formed part of the review process in putting this PQ-VCP inspection proposal together. A summary block flow diagram of existing Inspection Process used by PQ teams is provided in Figure 1 below: -


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Figure 1: Outline flow diagram for PQ Inspection process

1. Application to PQ

2. Dossier screening (completeness) check

3. Desk review of dossier & set up of PQ inspection team

4. Notify M/F of inspection scope and date(s)

5. Pre-approval Inspection at Manufacturing facility

Actives and Formulation Site(s)

6. Generate and distribute inspection report

7. Corrective actions and follow-up inspection reports

9. Maintenance of PQ Listing

Obligations of Industry

Post-marketing Activities o Routine inspections, Special inspections,

handling complaints o Sampling and testing o Handling variations (post-approval changes)

8. Decision on PQ Listing

Publish reports (WHOPIR/WHOPAR) on web site

Yes

No

8a. Add to PQ listing on web site. Publish reports (WHOPIR/WHOPAR) on web site


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1. Application to PQ

The evaluation process begins with the submission of application for a new product or variation to an existing product. The application can then be reviewed for technical assessment and site inspection assessment.

2. Screening (completeness) check

A check is conducted that the application contains all necessary and required documentation before detailed PQ review starts. The timeline between application completeness screening and generation of an inspection report is typically 6 months. This allows for at least one round of dossiers review so that issues that need to be assessed on site are flagged to the inspection team. Risk management principles are applied by the PQ team, using published risk assessment protocols, to evaluate prioritization and frequency of site inspections.

3. Desk review of Dossier and set-up of Inspection team. The lead inspector is always a WHO-PQ Staff member. One of the key submission documents for the lead Inspector conducting this desk review is the site master file (SMF). The SMF, also referred to as the Quality Manual, provides information on the layout and design of the manufacturing facility and allows a better understanding of the flow of material, personnel, and processes used within the facility. The review should also evaluate any previous inspections that may exist (e.g. internal audits, reports from National Inspectorates, etc.). The inspector may request additional information from the applicant in order to finalize an Inspection plan. The desk review will allow the Inspector to determine the scope and scale of the inspection and also the expertise needed at the site during the inspection. The Inspection team will normally consist of: -

Lead Inspector (WHO-PQ staff member)

External Inspector(s) from a well-established Inspectorate (Pharmaceutical Inspection Co-operation Scheme (PIC/S) or Medical Device Single Audit Programme (MDSAP)). The WHO maintain SOP’s related to the training and experience requirements for inspectors and also a list of available inspectors by country.

Technical expert(s) to support the Inspector on site

National Inspectors of the host country invited to be part of and/or be an observer of inspection.

Observer(s). Inspectors from countries where prequalified products are likely to be used are invited to participate as observers. This is for capacity building and also for them to appreciate the PQ process so that they can use the outcome for national registration.


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Appointed inspection team members (inspectors, technical experts and observers) have to treat all information submitted and observed during site inspections, as strictly confidential and proprietary to WHO or applicants. All external members of the inspection team have to sign a confidentiality undertaking and statement of declaration of interest before they participate in the inspection. The curriculum vitae of the inspection team are shared with the site before the inspection.

4. Notify manufacturing facility of scope of inspection and proposed date(s)

The lead inspector will co-ordinate with the Manufacturing facility (M/F) site leader and agree on the dates for the site inspection. A period of notice of 6 to 8 weeks is usually given to the M/F site but it may depend on the specific production plan of the M/F site. Ideally the product related to the submission should be being manufactured at the time of the inspection. If that is not feasible then at least a similar product type, using the same manufacturing process and packaging operations, should be being manufactured during the inspection. The length of the inspection will depend on the complexity of the production process but for a new product a period of 3-5 days would be typical.

In advance of the visit to the site the lead inspector will generate a proposed inspection plan and distribute this document to the inspection team members and the M/F site leader. The curriculum vitae of the inspection team are shared with the site before the inspection.

5. Pre-approval Inspection at Manufacturing facility

Pre-inspection and post-inspection meetings with the production site management are conducted. Inspections will follow the original inspection plan as far as possible.

The principal quality standard used for inspection of manufacturing sites for medicines and vaccines is GMP (Good Manufacturing Practice). For diagnostics the principal quality standard is ISO 13485:2003 which is specific to the quality systems and regulatory requirements of medical devices. WHO also maintains a wide selection of International norms and standards covering such topics as

Quality Assurance of Pharmaceuticals: a compendium of guidelines and related materials

WHO GMP for Active Pharmaceutical Ingredients which is identical to ICHQ7 GMP – Guide for Active Pharmaceutical Ingredients

WHO guidelines for drafting a site master file

These norms and standards may also be used by WHO-PQ during inspections.

Pre-approval inspections have the following specific objectives:


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Evaluation of the establishment’s compliance with GMP requirements, particularly regarding proper environment, quality management, personnel, facilities and equipment.

Evaluation of the procedures and controls implemented in the manufacture of the product (pre-approval batches), to determine whether they are in conformity with the dossier application commitments.

Audit of the completeness and accuracy of the manufacturing and testing information submitted with the application, and of the conformity of pre-approval batches with planned commercial batches (process validation protocol).

Collection of samples for the validation or verification of the analytical methods used

Further details of the procedures used for carrying out an inspection are given in WHO guidelines (Appendix A, #1,#2).

6. The inspection report

Within 4 weeks the lead inspector will prepare a report which includes a factual and objective record of the inspection procedures, the observations or findings for each activity inspected, as communicated to the company before the end of the inspection, and the conclusions drawn by the inspection team. Any deficiencies will be reported and the need for any corrective and preventive action (CAPA) documented.

Further details of the procedures used in preparing an inspection report are detailed in a WHO guideline (Appendix A, #5).

7. Corrective actions and follow-up inspection reports

If the inspection identifies deficiencies, these must be rectified, and a report issued from the M/F site management, detailing any corrective actions and follow-up that have been put in place. This report is normally required within 4 weeks of the Lead inspectors report. Depending on the seriousness of the deficiencies and comprehensiveness of the response from the M/F a follow-up inspection of the site may be instigated by WHO-PQ. The final outcome of the inspection is communicated in the inspection closing letter.

8. Decision on PQ listing

A PQ listing will be granted if the technical documentation (assessment) and site inspection evaluation for the product meet the WHO-PQ requirements. After a positive decision a WHO Public Assessment Report (WHOPAR) and WHO Public Inspection Report (WHOPIR) are published on the WHO-PQ website. The dossier applicant will have the opportunity to review these reports. A WHOPIR reflects the inspection performed and gives a summary of the observations and findings made during the inspection, but excludes confidential proprietary information.


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If a PQ listing is not granted, either because of issues with technical dossier contents and/or inspection of M/F facility, then applicants will need to consider a resubmission process.

9. Maintenance of PQ listing

(i) Obligations of Industry following Pre-Qualification

Requirements may vary according to the product type (medicines, vaccines, or diagnostics) but the main obligations common to most product types are to:

Notify any change (variation) in quality system, process or specification

Provide production and distribution data on an annual basis

Provide any new external inspection/audit reports

Implement and communicate an effective post-market surveillance system.

Establish a documented procedure for a feedback system to provide early warning of quality problems and corrective action/preventive action processes put in place.

Collect and evaluate any complaint received about the product (safety, quality or performance), and undertake any necessary corrective and preventive actions.

(ii) Re-inspections

For products with a WHO PQ listing there are processes in place, including re-inspection of M/F site(s), to maintain this PQ status. The types of re-inspection include: -

Routine re-inspection (typically every 1-3 years but will depend on risk assessment)

Follow-up inspection (where applicable to close out deficiencies from the last inspection, typically within 6 months of last inspection)

Special investigation – (following market complaints, sample inspection quality issues et al.)

In extreme cases where re-inspection finds critical deficiencies or that major quality issues have not been resolved a Notice of Concern (NOC) may be issued and published on the WHO website. An NOC can be issued as a result of: -

concern regarding compliance of the site with specified standards

an inadequate response to the observations noted in a PQ inspection report that details the corrective actions needed

refusal of a manufacturer to allow re-inspection of a manufacturing site.

(iii) Sampling and testing of PQ listed products

Field sampling and testing projects are carried out by the WHO Prequalification Programme (PQP) in order to:

monitor the quality of products against specifications


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contribute to national quality control, and

contribute to strengthening of health systems and capacity building

follow up complaints from the field and reports of adverse events

If a product fails to meet the established criteria, WHO will investigate the problem and provide the United Nations agency with written information, copied to the manufacturer and the NRA, on the actions that need to be taken.


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10. Introduction to Pesticide Vector Control Products (VCP’s)

Active Ingredients used in VCP’s The main active ingredients used in VCP’s are pesticides (primarily insecticides) produced by chemical synthesis. These synthetic chemicals are generally manufactured in plants where other pesticide active ingredients (plant protection pesticides) are also manufactured. The chemical synthesis used for their production is similar to that for pharmaceuticals; and the production route is usually a batch process with the specification based on analysis of the final product. The batch sizes and manufacturing plant vessels are normally much larger than in pharmaceutical production and the final purity is typically lower (94-98%) than that of a pharmaceutical active ingredient(>99%).

Bio-pesticide(bacterial) active ingredients (e.g. Bacillus thuringiensis(Bt)) are also used in VCP’s, principally as larvicides. These actives are typically manufactured in a dedicated fermentation plant and do not have any chemical synthesis process stages. These active ingredients are also used in the production of both plant protection and public health formulations.

The specifications of pesticide active ingredients would typically contain information on identity tests, active content (purity minimum), toxicologically relevant impurities (maximum allowed), other impurities (maximum allowed) and where applicable stabilizer content. For pesticides the nearest equivalent to the Pharmacopeia is the specifications published by the FAO/WHO (JMPS). The FAO and WHO specifications cover Agricultural (FAO) and Public Health (WHO) uses. However, the scope of these specifications are narrower than Pharmacopeia specifications in the following respects:

i) In most cases FAO_WHO specifications are not generated by Industry until the active ingredient is either off patent or close to patent expiry date.

ii) For many regulatory authorities complying with the FAO_WHO specification is not a mandatory requirement for getting an approval

iii) Only toxicologically relevant impurities are made public in the specification. The levels of other impurities and the manufacturing process remain confidential and are not disclosed by Regulatory Authorities.

iv) FAO_WHO specifications do not cover raw materials or co-formulant excipient’s.

In most cases the technical active ingredient is the starting material for formulation production. However, in some cases, an active ingredient manufacturer may be providing a concentrate of the active ingredient, usually to make it convenient and easy to handle by the formulation facility.

Unlike pharmaceuticals or vaccines the production of pesticide active ingredients does not need to be conducted under strictly controlled hygiene conditions.


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Formulation products used in VCP’s

The formulations manufactured for Vector Control include uses as larvicides, adulticides (e.g. indoor residual sprays, space sprays, vapour release devices), and Long Lasting Insecticidal Nets (LLIN’s). A more detailed review of the formulation types and uses can be found in the WHO guideline “Pesticides and their application for the control of vectors and pests of Public Health importance, 2006”, WHO/CDS/NTD/WHOPES/GCDPP/2006.1.

From a manufacturing viewpoint these formulations can be split into the 2 main types

Long Lasting Insecticidal Nets (LLIN’s)

Direct Treatment Formulations (Larvicides, IRS, Space sprays etc.)

i) Long Lasting Insecticidal Nets (LLIN’s)

A Long Lasting Insecticidal Net (LLIN) is a mosquito net impregnated with one or more insecticides. It is typically a slow- or controlled-release formulation in the form of netting, providing physical and chemical barriers to insects. Insecticide treated nets therefore provide two levels of protection. First as a mechanical barrier against the bites of disease-carrying mosquitoes and second as a means of killing mosquitoes on contact with the insecticide. There are two main production processes used in bednet manufacture: - i) Production of netting (consisting of mono- or multifilament fibres) from polymer

that has insecticide incorporated into the filaments ii) Production by coating of finished netting with insecticide

The final stage of mosquito bednet production is sewing and stitching of netting to form the finished product. Combination LLINs are also manufactured. These are long-lasting insecticidal nets made of different types of netting material, such as coated and incorporated, and/or netting material, with separate parts treated with different active ingredients. The various stages of the bednet process can be made at one location but often the production is done at different facilities, with the sewing and stitching and packing of final nets being the last stage of production. In some LLIN products there may be more than one insecticide and/or a synergist present in the finished product. A specification for a LLIN will include pesticide active(s) content, including durability of VCAI on the net (wash resistance index); there is also a strong focus on tests that measure the quality and strength of the net material (fabric weight, bursting strength, dimensional stability, etc.)


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The production process, manufacturing facilities, and the specification tests for LLIN’s are different to all other VCP formulation types. Recently a new type of formulation, coded MR – Matrix release formulation, has been developed. These MR’s are slow or controlled release formulations of a polymer coated with or containing incorporated insecticide. These formulations are for public health protection and aim to realize long lasting insecticidal efficacy after application into the habitat of harmful pests, for example, a water source, pond, water jar or well. Work to develop specifications is ongoing but, as yet, no WHOPES assessments of this formulation type have been published. ii) VCP Direct Treatment Formulations

These are generally formulations for spraying or spreading to control developing or adult mosquitoes. The table in Appendix B provides descriptions of the various formulation types that are currently listed (Aug 2016) on the WHOPES website for various vector control treatments. The manufacturing processes used for the preparation of these various formulation types are similar to those for some pharmaceutical formulated products. The formulation processes used include: -

Micronizing or milling

Dissolution in solvent

Mixing and blending

Emulsion preparation – high shear blending

Agglomeration and granulation

Tableting

In most cases the formulation process does not involve any chemical reactions. The exception is Capsule Suspensions where part of the formulation process involves a polymerization reaction which encapsulates the insecticide inside a polymer shell.

In some VCP’s there may be more than one insecticide and/or a synergist present in the finished product. The restrictions on co-formulant components used in VCP’s are generally less than those in medicines. This is mainly because VCP’s are not used for human consumption and are designed to be used by professional applicators. Therefore, for example, petroleum based solvents can typically be used as a co-formulant in VCP’s. Nevertheless, pesticide regulatory authorities are paying increasing attention to the use of safer co-formulants. The co-formulants used in pharmaceuticals are generally materials that have defined globally accepted Pharmacopeia specifications and this is not the case for co-formulants used in VCP formulated products. The production route for these VCP formulations is usually a batch process with the specification based on analysis of the final product. Batch sizes and manufacturing plant


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vessels are normally much larger than in pharmaceutical production; VCP’s are generally made and packed in the same manufacturing facility as Plant Protection Products. The specifications of these VCP’s typically contain information on identity tests, active content (purity minimum), and physical tests (CIPAC methods) according to the formulation type and method of application. For pesticides formulations, similar to pesticide active ingredients above there is no equivalent to the Pharmacopeia publications on Final Formulated products. However, many Regulatory Authorities will require applicants to follow the specification testing of formulation types as outlined in the Manual on development and use of FAO and WHO specifications for pesticides. First edition − third revision, March 2016

Unlike pharmaceuticals or vaccines, the production of pesticide VCP’s does not need to be conducted under strictly controlled hygiene conditions.

11. Review of VCP regulatory requirements for inspections/production processes

There are significant differences in the regulatory requirements for pesticides compared to those for pharmaceuticals or vaccines. The key differences, which relate to manufacturing and inspections are discussed below.

1. Manufacturing Process details

All of the manufacturing process details provided in a regulatory submission for VCAI’s and VCP’s are confidential and are not made public by the regulatory authority. For a vector control active ingredient dossier, it is necessary to provide a comprehensive description of the manufacturing process (without the engineering details) that includes details of synthesis steps, block flow diagrams, and information on pressures and temperatures for reaction steps. The level of detail on critical stages of the manufacturing process, and control of materials is minimal compared to that for medicines. Finally, unlike medicines, there is no requirement to provide information on process development or process validation for pesticide active ingredients. This does not mean that such information is not available from the applicant; only that it is not a regulatory requirement to provide such information.

Methods of analysis for pesticide active ingredients are required to be validated by GLP or to other recognized standards (e.g. CIPAC, ASTM, ISO, etc.). The GLP validation requirements for methods are different to GMP. There is no requirement to provide information on analytical methods or on stability of in-process intermediates in the manufacture of VCAI’s. The specification of pesticide active ingredients is based on evaluation of any toxicology test batches in combination with representative manufacturing batch analytical characterization of purity and impurities.


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There is no requirement to provide any details of the manufacture of pesticide VCP formulations except for the Confidential Statement of Formula (CSF) and a short description (block diagram) of the production process. In most cases the starting material for pesticide formulations is the technical active ingredient. However, in some cases the active ingredient supplier may provide a manufacturing concentrate to formulators as the starting material.

2. Manufacturing Inspections

An inspection of the manufacturing facility (of VCAI’s or VCP’s) is not a current requirement for regulatory approval. Inspections of these manufacturing facilities may be required by other National agencies, but the focus is then mainly on Human and Environmental Safety, rather than effectiveness of the manufacturing facility in producing quality products. Most Pesticide Regulatory Agencies will have a post-marketing program of sampling and testing the quality of formulated products. In most cases samples will be taken from distributor’s shelves and tested at authority approved laboratories. The annual program will include routine monitoring testing, dealing with complaint samples and, in the EU, testing of parallel import products. However, the program only tests a fraction of the products available on the market and the focus of the evaluations is often only on the active content of the product. There are no sampling and analysis post-market surveillance programs for Pesticide Active Ingredients. For medicines there is a requirement to organize continuous programs of stability testing of manufactured active ingredients and finished products. For pesticides stability data needs to be provided at submission (accelerated storage and 2-year shelf-life data) but there is no requirement for a running stability program on manufactured batches at each site. In most cases pesticide regulatory authorities only require stability data on the final formulated product and not on the technical active ingredient. Since there are no regulatory requirements for Quality Inspections of Manufacturing sites of Pesticides this means that there is

i) no set specific Quality standard that all manufacturers have to adhere to ii) no scheme like the PIC/S to call on to provide Inspectors for site audits


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12. Proposal for the Quality Standard to be used for VCP’s (actives and formulations)

The principal quality standard used for inspection of manufacturing sites for medicines and vaccines is GMP (Good Manufacturing Practice). A list of the key sections of a GMP audit are shown in Appendix C. For diagnostics the principal quality standard is ISO 13485:2003 (transitioning to 13485:2016 over next 3 years) which is specific to the quality systems and regulatory requirements for medical devices. Many organizations involved with medical device development, including manufacturers and service providers use ISO 13485 to "demonstrate [their] ability to provide medical devices and related services that consistently meet customer and applicable regulatory requirements." Regulators worldwide have integrated ISO 13485 into their regulatory systems, including those in the US, EU, Canada, Australia and Japan. The standard is sometimes adapted to meet local requirements, for example, EN ISO 13485:2012 in the EU adds a foreword and several annexes to the standard specific to the region. ISO 13485 is also used for the Medical Device Single Audit Program (MDSAP), an international effort to reduce redundant audits of medical device manufacturers. In the EU, GMP is also the quality standard used for inspection of veterinary product manufacturing sites. However, there is an exemption for those active ingredients which are used as ectoparasiticide1 treatments on domestic animals. In such cases there needs to be an audit of the Quality Management System used at the VCAI manufacturing site and a declaration by a Qualified Person (QP) that the audit was satisfactory. All veterinary final formulated products need to be manufactured to GMP. The Australian code for GMP for Veterinary chemical products also has provisions to allow veterinary products containing poisons (pesticides) to be manufactured at medicine production facilities providing it is:

in a segregated area/separate building

preferably uses dedicated equipment (or managed using production by campaign)

documented procedures to control contamination by a validated cleaning procedure exist

Australian veterinary chemical manufacturers (active ingredients) need to comply with the GMP code to apply and retain a manufacturing licence. Therefore, veterinary chemical manufacturers in Australia is monitored by APMVA authorized auditors. Auditors are recruited based on their experience, qualifications and familiarity with the Manufacturing Principles (link is external) and the GMP Code. WHO-PQ conduct training workshops and joint audits and, on occasion, send APVMA staff to audits, as observers. The APVMA operates an Overseas GMP Scheme for overseas manufacturers of veterinary chemical products supplied to Australia. Under this scheme, overseas manufacturers need to prove they meet GMP standards equal to those applied to

1 The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice. Brussels, 03 February 2010

ENTR/F/2/AM/an D(2010) 3374 page 5 “In the case of ectoparasiticides for veterinary use, other standards than these guidelines, that ensure that the material is of appropriate quality, may be used.”


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manufacturers in Australia. The APVMA assesses overseas sites’ GMP compliance as part of the registration process and as an ongoing compliance activity over the life of the product. The FAO and the WHO have produced a wide range of guidance documents covering pesticide registration and data requirements, quality control, compliance and enforcement, procedures for procurement/tenders, and post registration surveillance of pesticides. None of these guidance documents include any text on inspection of pesticide manufacturers. Most of the guidelines focus on the post-marketing compliance of products, recommending that appropriate sampling and analysis procedures are put in place by authorities and inspection agencies. For pesticide formulated products (excluding active ingredients used as veterinary ectoparasitics), there are no regulatory requirements for specific quality standards to be used by manufacturers, nor is there any requirement for inspection (pre- or post-approval) of manufacturing facilities. The majority of pesticide active ingredient manufacturing and formulation companies will have their own systems of quality management in place; there is no standardization of quality management systems throughout the industry. Most companies who use a specific externally audited quality management system are using one based on ISO 9001; a certified quality management system for organizations who want to prove their ability to consistently provide products and services that meet the needs of their customers and other relevant stakeholders. As pesticides are not currently required to be manufactured to GMP standards (with exception of pesticide veterinary products described above), there is no existing inspection infrastructure, nor are M/F plants exclusively dedicated to manufacture of a single product. Use of GMP as an inspection standard is unlikely to be practical or acceptable as its requirements are far more onerous than the current regulatory requirements. The PQ-Diagnostics team use an ISO standard (ISO 13485:2003/2016) as the quality standard for Inspections. This ISO 13485 standard is based on ISO 9001 requirements. Inspections of diagnostics products focus on whether processes and procedures in use by manufacturers are capable of ensuring the reliable supply of products to WHO Member States. It is clear however that any PQ Inspection process for VCP’s would require a quality standard to audit against. This report proposes that the quality standard to be used for PQ Manufacturing Inspections of VCP finished formulations should be based on the ISO 9001 Standard. The latest published version is ISO 9001:2015 but many facilities have certificates based on previous audits (e.g. ISO 9001:2008). The key requirements of ISO 9001 Standard are summarized in Appendix D of this report It is recognized that it may take a period of time, perhaps 3 to 5 years, for VCP product manufacturing sites to be aligned and have an ISO 9001 quality standard in place. In the meantime, it should be possible to inspect these facilities against the quality principles


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outlined in ISO 9001. The complexity of inspecting product formulations which are manufactured in different stages at different sites (e.g. LLIN’s) will need further consultation and discussion with Industry. The feasibility of requiring VCAI manufacturing sites to comply with the ISO 9001 quality standards will also need further discussion with Industry. In general, the public health uses of these insecticide active ingredients account for only a very small proportion of the overall production volume and so imposing a separate quality standard on Industry may be impractical and/or uneconomic. However, it should be feasible to conduct site inspections that follow the quality principles of ISO 9001, even if a facility does not hold ISO 9001 certification. The EU will allow manufacture of ectoparasitic active ingredients to be made at a non GMP facility, providing that the manufacturer of the finished formulated product conducts a quality audit of the a.i. site. A process similar to that used for these Ectoparasitic active ingredient insecticides in the EU may be a possible solution for Vector Control active ingredients. If the ISO standard used by the manufacturer is a superseded version of the recognized standard, the manufacturer should not be required to take any action unless there are safety implications, in which case the manufacturer should implement a risk mitigation strategy and take appropriate action to address these safety concerns. If a manufacturer chooses not to apply a recognized standard in part or in full, this may be acceptable if conformity with the Essential Principles can be demonstrated and/or the manufacturer can demonstrate that the standard or its parts are not applicable to the VCP under assessment. ISO 19011 is the document which gives guidance for performing both internal and external audits to ISO 9001.


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13. Proposal for PQ Inspection Process for VCP’s (actives and formulations)

All VCP submissions for new products and generic products will generally always require a site inspection as part of the PQ work process. Variations involving a change in manufacturing site will also need an inspection of the facility. A WHO guideline on variations to a prequalified product already exists (Appendix A, #9). This guideline will be reviewed and adapted/ amended to include variations in VCP prequalified products Over the longer period the PQ VCPAG will generate audit reports on inspected manufacturing sites. This audit information can then be used to determine whether a further site inspection can be waived. For example, a site that has already been audited for manufacture of a LLIN by a specific process may not require further inspection if a new product is introduced that is manufactured by the same process. A separate report will be prepared that will propose a risk assessment process to be used when considering the priority and need for conducting site inspections.

It is not anticipated that there will be significant differences between active ingredient and formulation manufacturing sites, in terms of the quality principles used for the inspection. Detailed SOP’s for VCP inspections will be prepared and information detailing the various work processes will be published on the WHO PQ VCAPG website. The outline flow diagram of the Inspection Process for VCAI’s and VCP’s can remain essentially the same as for other PQ inspections for medicines, vaccines, and diagnostics (see Figure 1 and Appendix E). For all submissions that require a site inspection it is expected that the typical timeline to complete and issue the inspection report will be 6 months after dossier screening is complete and the dossier is accepted for assessment. The following provides a summary of the key activities of the PQT vector control inspection process. The PQ Inspection process activities for VCAI’s and VCP’s can be similar to those of the other PQ teams on medicines, vaccines, and diagnostics. Therefore, these inspections can be considered in the following key stages: - i) Desk audit – preparing for an Inspection ii) Forming Inspection Team iii) Pre-approval inspection iv) Post PQ listing activities


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i) Desk audit – preparing for an inspection

A desk audit will help the Inspector to understand the processes used at the Manufacturing site, expertise that may be needed, and to draw up a draft inspection plan for the site. The following dossier information will be helpful to the Lead Inspector to conduct an effective desk audit of a VCAI/VCP Manufacturing facility.

a) Contact information on the manufacturer b) Detailed description of manufacturing process for proposed PQ

product(s) c) Proposed specification, justification of specification, GLP and/or

CIPAC validated methods d) Authorized manufacturing activities of the site. e) The quality management system of the manufacturer (including

release procedures, supplier’s management, external audits, etc.) f) Personnel on Site (Organizational Chart, etc.) g) Premises and Equipment h) Description of Documentation System used i) Production information (including material management, reworking

procedures, etc.) j) Quality Control (testing procedures) k) Procedures – Distribution/Complaints/Recalls l) Internal Audits

The lead inspector will use the dossier information to verify the objective of the inspection and decide the scope and depth of the inspection (e.g. inspecting part or all of the manufacturing facility). Any issues of concern will be communicated to the manufacturer. Based on the desk review a tentative Inspection plan will be prepared by the lead inspector.


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ii) Forming Inspection Team

The inspection team will be formed by the lead inspector and the team members will vary depending on the scope and depth of inspection as well as the product type being manufactured. It is anticipated that the typical Inspection team will consist of

The lead inspector o always a staff member of PQ

External Inspector(s) o an experienced auditor/inspector

from a local or International inspectorate ISO 9001 inspector from QMS auditing company

Technical expert(s) o Active Ingredients

Process Chemist/ Engineer and/or Analytical Chemist Production Biochemists (Bio-pesticides)

o LLIN’s – barrier type formulation Chemist and/or textile engineer

o Others – formulations for application Formulation chemist or Quality Control expert

Observer(s) o Interested parties from Local Inspectorates or Regulatory Authorities

As for other PQ units, it will be necessary for the PQ VCPAG unit to prepare and maintain lists of available and suitably qualified external inspectors and technical experts, on whom they can call to assist with site inspections. It will be important to address confidentiality and conflict of interest matters at the time of recruitment of external experts. There will be a need to provide to the inspected party the CV and any declared interests before the inspection (at the time of announcing the inspection) with an opportunity to consent or object to their participation. Members of the Inspection team will be given the tentative Inspection plan provided to for review and comment. The next stage will be for the lead inspector to provide an inspection plan to the manufacturer.


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iii) Pre-approval inspection

This site inspection is to allow the evaluation of the effectiveness of the quality management system and production processes implemented on site. The time needed to conduct a site inspection will obviously depend on a number of factors but an initial inspection can be expected to be 3 to 5 days. In most cases the inspection should coincide with the ongoing production of the PQ product being evaluated, or at least a product that uses a similar manufacturing process and testing procedure.

Following the initial introductions from both sides the following will be the key areas included in a typical inspection plan: -

a) Initial Tour of Facilities from goods receipt to final product and distribution b) Document control processes c) Supplier management for key raw materials d) Quality plan review (CAPA, Continuous Improvement) e) External and internal audit review f) Personnel and training g) Process validation (Reprocessing or Reworking) h) Quality Control testing – physical/chemical/biological i) Distribution/Complaints/Recalls

The lead inspector may arrange for samples to be taken as part of the inspection process and for them to be analyzed at an independent facility, to confirm the product meets the required specification. The deficiencies note shall be brought to the attention of the site management during the inspection and at the closing meeting. An inspection report will be prepared by the lead inspector which will include providing the manufacturer with findings (non-conformities, deficiencies, or observations). The manufacturer will be requested to prepare and submit a Corrective and Protection Actions (CAPA) report. The inspectors report will be provided within 4 weeks of the site audit and the responses from the management of the manufacturing site will be required within 4 weeks of receiving the report. In some cases, a follow-up inspection may be needed depending on the level of concern of the CAPA’s in the initial inspection report. Once PQ are satisfied with the technical assessment and the site inspection a PQ listing on the WHO PQ VCPAG web site will be published. Public assessment reports (WHOPAR/WHOPIR) will also published on the website. A WHOPIR reflects the inspection performed and gives a summary of the observations and findings made during the inspection, but excludes confidential proprietary information as well as all the individual observations that were communicated in the full inspection report.


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iv) Post PQ listing activities

Vector Control Products which are PQ listed will require their status to be maintained. A series of detailed guidelines on maintaining PQ listing of VCP products will be prepared but the key activities are summarized in the table below.

Post PQ listing Activity Responsible party Timing/Frequency

Notification of any change (variation) in manufacturing

Industry applicant, to notify WHO-PQ

Immediately or annually (see WHO guideline, Appendix A, #9)

Provide new external/internal audit reports of site facility

Industry applicant, to provide to WHO-PQ

Within 8 weeks of final audit report publication.

Provide report on quality problems, CAPA’s put in place

Industry applicant, to provide to WHO-PQ

Annually

Implement an effective post-marketing surveillance system

Industry applicant Annual report of findings for first 3 years of commercialization

Investigate any complaints or adverse events promptly and report results to all concerned parties

Industry applicant and WHO-PQ

Depends on nature of complaint or concern. WHO-PQ may request Industry to co-ordinate independent analysis.

Routine re-inspection of site facility

WHO-PQ Depends on risk assessment but no longer than 3 years since last inspection

Follow-up inspection of site facility

WHO-PQ Where applicable – typically 6 months or less from last inspection.

Special Investigation inspection of site facility

WHO-PQ (complaints, quality issues in marketplace, etc.)

Normally conducted at short notice depending on level of concern.

Notice of Concern (NOC) WHO-PQ Issued if WHO-PQ, following detailed investigation and discussion with applicant, are not satisfied that compliance to specified standards will be met.

Post-marketing sampling and testing of quality of VCP.

WHO-PQ Procurers, NRA’s, Country Inspectorates, etc.

Program of sampling and testing to be coordinated amongst interested parties.


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A separate report will be prepared that will propose a risk assessment process to be used when considering the priority and need for conducting site inspections and post-market surveillance sampling and testing.

14. Next steps in PQ VCPAG consultation

This report, and other reports that will discuss submissions on equivalency and site inspection risk management process, will form the basis of consultation with all interested parties including Industry (research and generic companies), procurement agencies, and national authorities. The current PQ-VCP inspection and post marketing activities proposed in this document are very similar to those used by other PQ teams and it is expected that existing guideline documents can be adapted to include VCP’s. Following the consultation process the key activities of the PQ VCPAG will include: -

Generation of final work process and timelines covering new products and, generic products

Publishing the risk assessment protocol that will govern frequency and site selection of post marketing inspections and sampling and testing of products from the market.

Establishing WHO lists of VCP technical experts and support Inspectors who can participate as members of a site inspection team

Develop (adapt) and publish WHO-PQ guidelines relating to VCP manufacturing quality, inspection processes, and post-marketing activities

Internal WHO SOP’s covering all inspection and monitoring activities will also need to be developed by the PQ VCPAG.


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Appendix A: Key WHO-PQ website reference guidelines The following website and WHO guideline references are the key ones used in this report on Inspection processes for VCP products. Links to all the guidelines are available on the WHO-PQ website pages.

Ref#

Reference details

1 The WHO PQ webpage - inspections

http://apps.who.int/prequal/assessment_inspect/info_inspection.htm

2 WHO Technical Report Series, No. 902, 2002 Annex 7, Guidelines on pre-approval inspections http://www.who.int/entity/medicines/publications/pharmprep/en/index.html

3 WHO TRS 823, Annex 2, Provisional guidelines on the inspection of pharmaceutical

manufacturers


4 Prequalification of in vitro diagnostics site inspections, Information for Manufacturers

on the Manufacturing Site(s) Inspection (Assessment of the Quality Management System) PQDx_014 v3 17 July 2014 http://www.who.int/diagnostics_laboratory/evaluations/140717_pqdx_014_info_manufacturers_pq_inspections_final.pdf

5 WHO Technical Report Series, No. 908, 2003 Annex 6, Guidance on Good Manufacturing Practices (GMP): inspection report http://www.who.int/entity/medicines/publications/pharmprep/en/index.html

6 World Health Organization Public Inspection Reports (WHOPIR) - webpage

http://apps.who.int/prequal/WHOPIR/pq_whopir.htm

7 WHO TRS 986, Annex 2 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-eighth report, WHO good manufacturing practices for pharmaceutical products: main principles

http://www.who.int/medicines/areas/quality_safety/quality_assurance/expert_committee/ISBN9789241209861-TRS986.pdf?ua=1


http://www.who.int/entity/medicines/publications/pharmprep/en/index.html


http://www.who.int/diagnostics_laboratory/evaluations/140717_pqdx_014_info_manufacturers_pq_inspections_final.pdf

http://www.who.int/diagnostics_laboratory/evaluations/140717_pqdx_014_info_manufacturers_pq_inspections_final.pdf


http://apps.who.int/prequal/WHOPIR/pq_whopir.htm




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Ref#

Reference details

8 Standards applicable to the WHO Prequalification of in vitro diagnostics

TGS–1, 17 March 2016 v2 www.who.int/diagnostics_laboratory/guidance/160321_tgs1_standards_v2.pdf

9 WHO Technical Report Series, No.961, 2011

Annex 14m WHO guidelines for drafting a site master file http://www.who.int/entity/medicines/publications/pharmprep/en/index.html

10 WHO Technical Report Series, No. 961, 2011 Annex 10, Procedure for prequalification of pharmaceutical products http://www.who.int/entity/medicines/publications/pharmprep/en/index.html

11 OVERVIEW OF THE PREQUALIFICATION OF IN VITRO DIAGNOSTICS ASSESSMENT PQDx_007 v5 30 May 2014 http://www.who.int/entity/diagnostics_laboratory/evaluations/140530_pqdx_overview_doc_007.pdf?ua=1

12 Variations (changes) to Prequalified Medicines - Procedural Guidance - webpage

http://apps.who.int/prequal/info_applicants/info_for_applicants_procedural-

guidance.htm

13 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report, Annex 3 WHO guidelines on variations to a prequalified product http://www.who.int/entity/medicines/publications/pharmprep/en/index.html

14 Post Market Surveillance of In-vitro Diagnostics, World Health Organization 2015 http://www.who.int/diagnostics_laboratory/postmarket/150819_pms_guidance_final_version.pdf

15 Annex 4 WHO Technical Report Series, No. 902, 2002 Considerations for requesting analysis of drug samples http://www.who.int/entity/medicines/publications/pharmprep/en/index.html

16 WHO Technical Report Series no 885, 1999, Annex 6, Guidelines for inspection of drug

distribution channels


17 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-seventh report, Annex 2, WHO guidelines on quality risk management http://www.who.int/entity/medicines/publications/pharmprep/en/index.html

http://www.who.int/diagnostics_laboratory/guidance/160321_tgs1_standards_v2.pdf



http://www.who.int/entity/diagnostics_laboratory/evaluations/140530_pqdx_overview_doc_007.pdf?ua=1

http://www.who.int/entity/diagnostics_laboratory/evaluations/140530_pqdx_overview_doc_007.pdf?ua=1

http://apps.who.int/prequal/info_applicants/info_for_applicants_procedural-guidance.htm

http://apps.who.int/prequal/info_applicants/info_for_applicants_procedural-guidance.htm


http://www.who.int/diagnostics_laboratory/postmarket/150819_pms_guidance_final_version.pdf

http://www.who.int/diagnostics_laboratory/postmarket/150819_pms_guidance_final_version.pdf





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Ref#

Reference details

18 WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-ninth report Annex 3, Guidelines on good manufacturing practices: validation, Appendix 7: non‐sterile process validation http://www.who.int/entity/medicines/publications/pharmprep/en/index.html

19 WHO Technical Report Series, No. 937, 2006 Annex 4, Supplementary guidelines on good manufacturing practices: validation http://www.who.int/entity/medicines/publications/pharmprep/en/index.html

20 WHO Technical Report Series, No. 957, 2010 Annex 6, Guidelines on the requalification of prequalified dossiers http://www.who.int/entity/medicines/publications/pharmprep/en/index.html

21 WHO PQ Inspections – Q AND A document

http://apps.who.int/prequal/info_general/documents/inspection/Q-A.pdf

22 WHO publication, 2015 Investing in WHO Prequalification of finished Pharmaceutical Products

http://apps.who.int/prequal/info_press/documents/WHO_Prequalification_WHY.pdf

23 Manual on development and use of FAO and WHO specifications for pesticides. First edition − third revision, March 2016 http://apps.who.int/iris/bitstream/10665/246192/1/WHO-HTM-NTD-WHOPES-2016.4-eng.pdf?ua=1

24 Good Manufacturing Practice (GMP) and related procedures applied by Australian Pesticides and Veterinary Medicines Authority (APVMA):

http://apvma.gov.au/node/72

http://apvma.gov.au/sites/default/files/docs/gmp_code_vet_0.pdf






http://apps.who.int/prequal/info_general/documents/inspection/Q-A.pdf

http://apps.who.int/prequal/info_press/documents/WHO_Prequalification_WHY.pdf

http://apps.who.int/iris/bitstream/10665/246192/1/WHO-HTM-NTD-WHOPES-2016.4-eng.pdf?ua=1

http://apps.who.int/iris/bitstream/10665/246192/1/WHO-HTM-NTD-WHOPES-2016.4-eng.pdf?ua=1


http://apvma.gov.au/sites/default/files/docs/gmp_code_vet_0.pdf




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Appendix B: Key VCP formulation types with WHOPES listed recommendation

Code Formulation type1

Formulation Description Vector Control uses

CS Capsule Suspension

A stable suspension of capsules in a fluid, normally intended for dilution with water before use.(as a spray)

Indoor Residual Spray

DT Tablet for Direct Application

Formulation in the form of tablets to be applied individually and directly in the field, and/or bodies of water, without preparation of a spraying solution or dispersion.

Larvicides

EC Emulsifiable Concentrate

A liquid, homogeneous formulation to be applied as an emulsion after dilution in water. (as a spray)

Larvicides, Indoor Residual Spray, Space Sprays

EW Emulsion, oil in water

A fluid, heterogeneous formulation consisting of a solution of pesticide in an organic liquid dispersed as fine globules in a continuous water phase (as a spray)

Space sprays

GR Granule A free-flowing solid formulation of a defined granule size range ready for use. (direct application)

Larvicides

SC Suspension concentrate

A stable suspension of active ingredient(s) with water as the fluid, intended for dilution with water before use. (as a spray)

Larvicides, Indoor Residual Spray

UL Ultra-Low volume liquid

A homogenous liquid ready for use through ULV equipment. Can be applied directly or with pre-dilution in oil. Can also be applied through fogging equipment

Space Sprays

WG Water dispersible granules

A formulation consisting of granules to be applied after disintegration and dispersion in water. (as a spray)


WP Wettable powder

A powder formulation to be applied as a suspension after dispersion in water. (as a spray)


1The full range of formulation types and descriptions are listed in the Manual on development and use of FAO and WHO

specifications for pesticides. First edition − third revision, March 2016


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Appendix C: GMP, Principle Audit Requirement sections

II. Quality Management III. Personnel IV. Buildings and Facilities V. Process Equipment VI. Documentation and Records VII. Materials Management VIII. Production and In-Process Controls IX. Packaging and identification labelling of API’s and intermediates X. Storage and Distribution XI. Laboratory Controls XII. Validation XIII. Change Control XIV. Rejection and re-use of materials XV. Complaints and recalls XVI. Contract Manufacturers (including laboratories) XVII. Agents, brokers, traders, distributors, repackers, and relabellers


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Appendix D: ISO 9001 Standard – Key Requirements - Summary

4 Overall Requirements for the QMS system 4.1 Set up quality management system: develop, use and improve it. 4.2 Document system - say how it should work. 5 Requirements for Management 5.1 Demonstrate commitment to the quality management system 5.2 Focus on customers 5.3 Write a quality policy. Use it. 5.4 Plan for quality 5.5 Define and communicate 'who does what' 5.6 Review quality management system at regular intervals 6 Resource Requirements 6.1 Decide what resources are needed for the QMS 6.2 Make sure people are competent: 6.3 Infrastructure: Decide what is needed - provide and maintain it. 6.4 Work environment: provide what is needed in services/products to ensure requirements are met 7 Requirements for Products or Services 7.1 Plan and develop the processes needed for products/services. 7.2 Have effective 'customer-related' processes: 7.3 Have effective processes for designing & developing products/services 7.4 Control what is purchased, outsource or subcontract 7.5 Manage all operations 7.6 Control measuring and monitoring equipment 8 Requirements for Analysis and Improvement 8.1 Have analysis and improvement processes to ensure services/products meet all relevant requirements. 8.2 Monitor and measure processes and services/products 8.3 Control nonconformity in suitable ways, including a written procedure. 8.4 Collect and analyze information 8.5 Continually improve.


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Appendix E: Principles of Pre-Qualification (PQ) Process The principle of the proposed PQ process outlined here for Vector Control products is based on that already used by the WHO-PQ teams in pre-qualification of medicines, vaccines, and diagnostics. This process is outlined in the flow chart shown below: -

Pre-submission

Dossier assessment

Site Inspection

Final PQ decision and PQ listing

PQ Maintenance of Listed products

Consultation Industry and WHO-PQ

WHO-PQ team with expert scientists - regular dossier review meetings

Manufacturing sites inspected – against quality management principles

Product dossier and manufacturing sites acceptable – product listed on WHO web site

Post marketing activities Sampling/testing, managing variations and

complaints, re-inspections, etc.

Field scale efficacy trials


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