EU, FDA and WHO Regulations Part Three, WHO Regulatory Requirements and Developments

The World Health Organization, sometimes better known simply as the WHO, conducts GMP inspections worldwide to promote and ensure affordable access to quality, safe and effective medicines.

To ensure that quality pharmaceuticals are available regardless of the wealth of a country, the WHO sets norms and standards, develops guidelines and advises Member States on issues related to the quality of medicines. The WHO also assists certain countries in building national regulatory capacity. WHO prequalification is an important component of these activities and mandate.

Until 2000, the pattern was “poor quality medicines for the poor”. Today, thanks to prequalification, millions of people suffering from HIV/AIDS, tuberculosis (TB) or malaria in low-income countries have access to world standard treatment."

The WHO Prequalification Team: medicines (PQTm) was first established ― as the then Prequalification of Medicines Programme ― in 2001, in response to the HIV/AIDS pandemic. Its aim was to guide UN agencies and other international organizations with respect to the quality of antiretroviral medicines, for supply to low-income countries.

Its services now cover assessment, not only of a range of finished pharmaceutical products, in several therapeutic areas, but also assessment of active pharmaceutical ingredients, and of quality control laboratories. It also provides technical assistance, conducts extensive training activities  (In 2013, the former Prequalification of Medicines Programme was merged with the WHO programmes for prequalification of diagnostics and of vaccines, to create the WHO Prequalification Team.)

UNAIDS, UNICEF, UNFPA and the World Bank ― and many other organizations ― consider WHO medicines prequalification to be a concrete contribution to the United Nations priority goal of addressing high-burden diseases in countries with limited access to quality medicines.

WHO Guideline Developments - 2018 

Over 2018, a large number of new documents have been published by the WHO. These include documents on water for injection (WFI), imports of pharmaceutical products and the WHO certification scheme on the quality of pharmaceutical products moving in international commerce for example. Below we will detail the most important changes over 2018.

The table below shows the most important developments:

OrganizationGuidance / Draft TitleStatus
WHOGOOD MANUFACTURING PRACTICES FOR HEATING, VENTILATION 4 AND AIR-CONDITIONING SYSTEMS FOR NON-STERILE 5 PHARMACEUTICAL DOSAGE FORMS: PART 2Draft Guidance
WHOInquiry regarding production of water for injection (QAS/18.764)Draft Guidance
WHOGuidelines for the safe production and quality control of poliomyelitis vaccineDraft guidance
WHOProposal for revision of the who certification scheme on the quality of pharmaceutical products moving in international commerce (QAS/18.768)Draft Guidance
WHOGUIDELINES ON IMPORT PROCEDURES FOR PHARMACEUTICAL PRODUCTSDraft guideline
WHOWHO TRS 1010 Annex 1 WHO guidelines on good herbal processing practices for herbal medicinesGuidance
WHOWHO TRS 1010 Annex 2 Guidelines on good manufacturing practices for the manufacture of herbal medicinesGuidance
WHOWHO TRS 1010 Annex 3 Considerations for requesting analysis of medicines samplesGuidance
WHOWHO TRS 1010 Annex 4 Model certificate of analysisGuidance
WHOWHO TRS 1010 Annex 5 WHO guidance on testing of “suspect” falsified medicinesGuidance
WHOWHO TRS 1010 Annex 6 Good pharmacopoeial practices: Chapter on monographs for compounded preparations  Guidance
WHOWHO TRS 1010 Annex 7 Good pharmacopoeial practices: Chapter on monographs on herbal medicinesGuidance
WHOWHO TRS 1010 Annex 8 Guidelines on heating, ventilation and air-conditioning systems for non-sterile pharmaceutical productsGuidance
WHOWHO TRS 1010 Annex 9 Guidance on good practices for desk assessment of compliance with good manufacturing practices, good laboratory practices and good clinical practices for medical products regulatory decisionsGuidance
WHOWHO TRS 1010 Annex 10 Stability testing of active pharmaceutical ingredients and finished pharmaceutical productsGuidance
WHOWHO TRS 1010 Annex 11 Collaborative procedure in the assessment and accelerated national registration of pharmaceutical products and vaccines approved by stringent regulatory authoritiesGuidance
WHOWHO TRS 1011 Annex 1 WHO Recommendations, Guidelines and other documents related to the manufacture, quality control and evaluation of biological substances used in medicineGuidance
WHOWHO TRS 1011 Annex 2 Guidelines on the quality, safety and efficacy of Ebola vaccinesGuidance
WHOWHO TRS 1011 Annex 3 Guidelines on procedures and data requirements for changes to approved biotherapeutic productsGuidance
WHOWHO TRS 1011 Annex 4 Technical Specifications Series (TSS) for WHO Prequalification – Diagnostic AssessmentGuidance
WHOWHO TRS 1011 Annex 5 Technical Guidance Series (TGS) for WHO Prequalification – Diagnostic AssessmentGuidance
WHOWHO TRS 1011 Annex 6 Biological substances: WHO International Standards, Reference Reagents and Reference PanelsGuidance

The highlights of these updates include; 

  • Inquiry regarding production of water for injection (QAS/18.764)
  • Proposal for revision of the who certification scheme on the quality of pharmaceutical products moving in international commerce (QAS/18.768)
  • WHO TRS 1010 Annex 2 Guidelines on good manufacturing practices for the manufacture of herbal medicines
  • WHO TRS 1010 Annex 8 Guidelines on heating, ventilation and air-conditioning systems for non-sterile pharma ceutical products
  • WHO TRS 1010 Annex 9 Guidance on good practices for desk assessment of compliance with good manufacturing practices, good laboratory practices and good clinical practices for medical products regulatory decisions
  • WHO TRS 1010 Annex 10 Stability testing of active pharmaceutical ingredients and finished pharmaceutical products
  • WHO TRS 1010 Annex 11 Collaborative procedure in the assessment and accelerated national registration of pharmaceutical products and vaccines approved by stringent regulatory authorities
  • WHO TRS 1011 Annex 3 Guidelines on procedures and data requirements for changes to approved biotherapeutic products

WHO (QAS/18.764) Inquiry regarding the production of WFI

  • Current situation for WHO:

–Monograph on “Water for injections” in The International Pharmacopoeia

–WHO good manufacturing practices: water for pharmaceutical use (TRS 970 Annex 2)

  • Other pharmacopoeias allow other technologies

–The Japanese Pharmacopoeia and the US Pharmacopeia, for example, allow for production of WFI by distillation or a purification process proven to be equal or superior to distillation, and by distillation or reverse osmosis followed by ultrafiltration, respectively.

–The European Pharmacopoeia foresees that the use of non-distillation technologies for the production of WFI requires that notice is given to the supervisory authority of the manufacturer before implementation

  • The new Annex 1 will include new guidance for WFI production

WHO (QAS/18.768) Proposal for revision of the WHO certification scheme on the quality of pharmaceutical products moving in international commerce

  • International voluntary agreement to provide assurance to countries participating in the Scheme about the quality of pharmaceutical products moving in international commerce.
  • The primary document of the Scheme is the Certificate of a Pharmaceutical Product (CPP)
  • The working document addresses key issues that need improvement

–Include EU, not only separate member states

–List of competent authorities out of date

–Certifying countries that do not fulfil the prerequisites required by the Scheme issue certificates to support approval of marketing authorization.

WHO TRS 1010 Annex 2 Guidelines on GMP for the manufacture of herbal medicines

  • WHO TRS 1010 Annex 2 is an update of the existing guidance, WHO TRS 937 Annex 3 (2006)
  • These new guidelines are intended to complement GMP guidelines for pharmaceutical products
  • The guideline relates specifically to the production and control of herbal medicines, in so far as they mainly focus on identifying the critical steps needed to ensure good quality
  • Ensure consistency with the current terminology used
  • Chapters and their content are not changed
  • EMA draft Guideline on quality of herbal medicinal products/traditional herbal medicinal products is not harmonized with the WHO guideline

WHO TRS 1010 Annex 8 Guidelines on HVAC systems for non-sterile 
pharmaceutical products

Guideline Scope:

  • The guideline focusses primarily on GMP for HVAC systems used in facilities for the manufacture of non-sterile dosage forms and will address the following:

–The design

–Qualification

–Management

–Maintenance

  • This guideline is intended to complement other guidelines on GMP for pharmaceutical products and should be read in conjunction with a parent guide.

Guideline Content: 

  • Premises
  • Design of HVAC systems and components
  • Full fresh air systems and recirculation systems
  • Air filtration, airflow direction and pressure differentials
  • Temperature and relative humidity
  • Dust, vapor and fume control
  • Protection of the environment
  • Commissioning
  • Qualification
  • Maintenance
  • Interpretation of Part 1: GMP For HVAC Systems
  • Sample drawings with background information:
    • Weighing area's
    • Sampling area's
    • Changing room
    • Compression cubicle with MAL and PAL
    • Washing area's
    • Example of airflow in a cleanroom
    • Pressure cascading
    • Airlocks

 WHO TRS 1010 Sampling Area SampleWHO TRS 1010 Washing Area Sample

WHO TRS 1010 Annex 9  Guidance on good practices for desk assessment of compliance with GMP, GLP and GCP for medical products regulatory decisions

Purpose and Scope: 

  • This guidance applies to all FPP and API manufacturers, QCL, CRO that are subjected to GxP inspections in foreign countries.
  • It covers the information and evidence required to undertake a desk assessment process
  • Objectives of the document:

–ensure that a standardized procedure is followed for desk assessment of inspection documentation and reports issued by trusted, competent regulatory authorities and of records of corrective actions from inspected sites

–facilitate a convergent approach and model for exchange and use of inspection information in national and regional decisionmaking concerning the necessity to perform preapproval and surveillance inspections

Content of the Document: 

  • Essential elements of desk assessment

–High-level support and cooperation

–Commonality of quality management systems in inspectorates

–Convergent standards of good practices

–Reliability and accuracy of information

–Management tools to support consistent and objective assessment

–Risk-based assessment of available information

–Mutual trust and confidence among inspectorates

–Quality assurance of the desk assessment process

–Communication of assessment outcomes

  • Sources of good information and related challenges

–Official websites with databases

–Authenticity of documents

–Failure to submit documentary evidence

  • Submission and assessment of documentary evidence and information

–Submission of application for desk assessment and documentary evidence

–Assessment of documentary evidence and information

–General requirements for documents

  • Regulatory actions and reporting of serious instances of noncompliance

–Communication and information exchange

  • Responsibilities of the applicant 

WHO TRS 1010 Annex 10 Stability testing of API and FPP

Importance of this Document: 

 Due to discussions on climate zones for global stability testing requirements, the ICH Steering Committee has decided to withdraw ICH Q1F and to leave definition of storage conditions in Climatic Zones III and IV to the respective regions and WHO

  • ICH Q1F refers to WHO Stability Guideline 2018

Scope: 

  • Applicable to new and existing APIs
  • Address information to be submitted in original and subsequent applications for marketing authorization of their related Finished Pharmaceutical Product for human use
  • The aim of this guideline is to outline the core stability data package required for registration of active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs)
  • It is recommended that these guidelines should also be applied to products that are already being marketed, for example, upon re-registration or upon re-evaluation

Content API: 

–General
–Stress testing
–Selection of batches
–Container-closure system
–Specification
–Testing frequency
–Storage conditions
–Stability commitments
–Evaluations
–Statements and labelling
–Ongoing  stability studies 

FPP adds: 

–In-use and hold time stability
–Variations

•Appendix 1 Examples of testing parameters
•Appendix 2 Recommended labelling statements
•Appendix 3 Interpretation of storage statements 

WHO TRS 1010 Annex 11 Collaborative procedure in the assessment and accelerated national registration of pharmaceutical products and vaccines approved by stringent regulatory authorities

Background Information:

  • Management of diseases known to be of major relevance to public health in countries with limited regulatory resources is often jeopardized by delayed access to new or needed therapies
  • To address this issue, WHO proposes a scheme for NRAs and pharmaceutical manufacturers to facilitate registrations of the vaccines and pharmaceutical products, including biotherapeutic products approved by reference Stringent RA’s
  • Pharmaceutical manufacturers benefit from accelerated and facilitated regulatory processes, but the shared data should will be treated with necessary care and respect for confidentiality by the NRA 

 

WHO TRS 1011 Annex 3 Guidelines on procedures and data requirements for changes to approved biotherapeutic products

Purpose and Scope: 

  • Provide guidance for NRAs and marketing authorization holders on the regulation of changes to the original marketing authorization dossier or product license for an approved biotherapeutic product in terms of: (a)

–The procedures and criteria for the appropriate categorization and reporting of changes

–The data required to enable NRAs to evaluate the potential impact of the change on the quality, safety and efficacy of the product

  • Changes to approved biotherapeutic products or SBPs are categorized on the basis of a risk analysis which takes into consideration:

–The complexity of the production process and product

–The patient population and

–The proposed changes

Content: 

  • General considerations
  • Special considerations

–Comparability exercise

–Bridging studies

–Similar biotherapeutic products

  • Reporting categories for quality changes
  • Reporting categories for safety, efficacy and/or product labelling information changes

–Safety and efficacy changes

–Product labelling information changes

–Urgent product labelling information changes

–Administrative product labelling information changes.

  • Procedures

–Procedures for prior approval supplements

–Procedures for minor quality changes and quality changes with no impact

–Procedures for urgent product labelling information changes

–Procedures for administrative product labelling information changes

Risk Based: 

  • Changes to approved biotherapeutic products or SBPs are categorized on the basis of a risk analysis which takes into consideration:

–The complexity of the production process and product

–The patient population and

–The proposed changes

WHO GMP Updates in 2019

So far the following GMP guidelines have been published by the WHO in 2019:

WHOGOOD CHROMOTOGRAPHY PRACTICESDraft1-FEB-19
WHOPRODUCTION OF WATER FOR INJECTION BY MEANS OTHER THAN DISTILLATIONDraft1-FEB-19
WHOENVIRONMENTAL ASPECTS OF GMPDraft guideline1-May-19
WHOQUALITY SYSTEMS REQUIREMENTS FOR NATIONAL INSPECTORATESDraft guideline1-May-2019

 

PCS will update on the content of these WHO GMP regulatory guidelines at the end of 2019