Inspections

Before prequalification of an active pharmaceutical ingredient (API) or finished pharmaceutical product (FPP) can be granted, WHO must assess whether the relevant manufacturing site(s) operate(s) in compliance with WHO Good Manufacturing Practice (GMP). This may be by on-site inspection or by leveraging the outputs of inspections conducted by national medicines regulatory authorities operating to equivalent standards and stringency. (See also Inspection Waiver.) WHO inspections are:

  • Risk based: All inspections shall be planned, performed, and, in the case of surveillance inspections, be at a frequency and level of detail that takes into account the nature of the products manufactured and the history of compliance of the respective site.
  • Leverage the experience of national medicines regulatory authorities operating to equivalent standards and stringency: Where satisfactory recent, relevant and reliable evidence of compliance is available to WHO this will be taken into account in the planning of on-site inspections and inspections may be waived or deferred.
  • Performed in collaboration with regulatory partners:  Whenever and wherever practicable WHO inspections:
    • maximize the use of scarce international inspection resources
    • leverage international inspection experience and expertise
    • maximize the usefulness of the inspection outcome
    • minimize the regulatory burden on those inspected.

Inspections of API or FPP manufacturing sites are restricted to GMP compliance in relation to the products submitted for prequalification.  All inspections are performed as a sampling exercise: that is, not each and every element of WHO GMP or all parts of a site will be examined, but only those elements of direct relevance to the product(s) submitted. More than one product may be assessed in a single inspection.

In the case of a generic FPP submitted for prequalification, inspection of the contract research organization (CRO) that conducted a clinical study for the product may also be necessary. Generally, this clinical study will have taken the form of a bioequivalence study, aimed at demonstrating therapeutic equivalence (i.e. efficacy and safety) with the innovator product. CRO inspections are therefore study-specific: each CRO inspection is linked to a study that was undertaken in relation to a specific product. During inspection of a CRO, compliance with WHO Good Clinical Practices for Trials on Pharmaceutical Products and WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies is assessed, and data verification performed.

WHO also inspects quality control laboratories (QCLs) that have applied for prequalification. QCL inspections are carried out to assess adherence to WHO Good Practices for Pharmaceutical Quality Control Laboratories (GPQCL), WHO Good Practices for Pharmaceutical Microbiology Laboratories and WHO GMP.

Post-prequalification surveillance inspections are undertaken routinely to verify that manufacturing sites are maintaining WHO GMP standards, or, in the case of complaints, as part of an investigation. The frequency and length of these routine inspedtions are determined according to quality risk management principles. Similarly, routine inspections of QCLs verify continued adherence to GPQCL, WHO Good Practices for Pharmaceutical Microbiology Laboratories and WHO GMP. Since CRO inspections are mainly study-specific, they are not subject to post-prequalification inspection.

WHO Public Inspection Reports —  posted on this website for all manufacturing sites, contract research organizations and QCLs that have passed inspection — are a key output of WHO medicines prequalification.

Our inspection principles

WHO inspections are guided by a number of principles:

  • Independence: Members of the inspection team shall be impartial and free from influences that could negatively affect their objectivity.
  • Inspection objectives and scope: The inspection objectives and scope shall be defined. A tentative inspection plan shall be provided to the manufacturer and agreed upon with the manufacturer before the inspection. Adaptation of the plan may occur, to accommodate the manufacturing site processes and to enable audit trails to be followed.
  • Roles and responsibilities: Roles and responsibilities of all personnel involved in the inspection shall be clearly defined so that expectations can be met and the accountability of each is understood.
  • Resources: Resources shall be adequate in terms of competent inspectors, expertise, time allocation and access to external technical and other information, thereby contributing to the reliability of the inspection results.
  • Competence of the inspection team: The inspection team shall consist of inspectors with auditing skills, and the education and experience in regulatory requirements that are appropriate for the inspections tasks assigned to them. Representatives of the national regulatory authorities, procurement agencies and other WHO employees may accompany the inspection team to the manufacturing site(s) as observers or for training purposes.
  • Consistency of procedures: The inspection shall be performed according to defined guidelines and led by a WHO inspector to ensure consistency during the inspection. The WHO inspector with overall responsibility for inspections shall ensure consistency between inspections of the same type and scope.
  • Adequacy of inspection documentation: Documentation associated with each inspection, such as inspection reports, shall provide adequate information related to the prequalification assessment of the product, for ensuring continuity between successive inspections and to assist the manufacturers in making quality improvements.
    • Confidentiality and standard of conduct: The inspectors shall maintain confidentiality with regard to information and documentation related to the inspection and shall comply with the defined WHO standards of conduct. Aside from these considerations, the inspection process should be transparent to all participants.
    • Inspection results and conclusions: The results and conclusions of the inspections shall be consistent and accurate, subject to the normal limitations of an inspection, and taking into account that the objective evidence collected during the inspection is generally a sample.

A WHO inspection team generally consists of:

  • the lead inspector (normally a WHO staff member)

  • a co-inspector who is trained, knowledgeable and experienced in carrying out inspections; co-inspectors are drawn from either a member Inspectorate of the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S), and/or inspectors of other NMRAs whose experience has been validated e.g. by involvement in the WHO rotational inspector or observed inspection programmes

  • observers who may include personnel from local or other inspection agencies, and inspection trainees; observers are not considered to be inspectors but must comply with the same standards of conduct as the inspectors; the number of observers will be limited to ensure minimal disruption to the inspection and to the manufacturing process

  • in addition, if required, qualified interpreters who facilitate communication between the inspection team and the manufacturer`s personnel, to support open and effective communication throughout the inspection.

Inspection roles and responsibilities

The lead inspector is responsible for all phases of the inspection. S/he has the authority to make final decisions regarding conduct of the inspection and observations made during the inspection. The lead inspector will normally be a WHO staff member. However, WHO may delegate this role to an external consultant when deemed appropriate.

During a WHO inspection, the lead inspector, co-inspector(s) and manufacturer, contract research organization (CRO) or quality control laboratory (QCL) each have responsibilities for ensuring the good conduct of the inspection and satisfactory inspection outcomes.

The lead inspector

In addition to the responsibilities of an inspector, as described below, the lead inspector:

  • plans and prepares the inspection
  • communicates with the manufacturer about the inspection
  • assists with the selection of the inspection team members
  • defines the scope of the inspection
  • prepares a tentative inspection plan, working documents and briefing documents and supervises the inspectors' travel arrangements
  • represents the inspection team with the manufacturer/CRO/QCL
  • supervises inspectors during the inspection
  • communicates any obstacles regarding the inspection to the manufacturer and to WHO before or during the inspection
  • prepares and presents the general inspection outcome, after consultation with the other inspectors, to the manufacturer/CRO/QCL at the closing meeting
  • compiles the final inspection report, after consultation with the other inspectors, for review and approval by the WHO officer with overall responsibility for inspections
  • sends the report to the manufacturer/CRO/QCL
  • follows up on the corrective and preventive actions (CAPAs) proposed and taken by those inspected regarding any observations made during the inspection
  • when applicable, verifies that corrective actions have been taken within agreed timelines and have been shown to be effective.

The co-inspectors

Each co-inspector:

  • uses established inspection methods to ensure consistency in the inspection process
  • plans and carry out assigned responsibilities objectively, effectively and efficiently within the inspection scope
  • safeguards confidentiality of documents and information during and subsequent to the inspection
  • complies with WHO standard of conduct
  • performs the inspection to achieve the objectives in a polite and enquiring manner, and is never discourteous or intimidating
  • complies with WHO prequalification requirements for inspections
  • collects, analyses and documents objective evidence to establish the extent of compliance with the quality system and the effectiveness of its implementation
  • establishes the extent to which the procedures, documents and other available information are understood and used by the manufacturer's/CRO/QCL personnel
  • brings to the attention of the lead inspector in a timely manner, any indications or observations that could influence the inspection results, require more in-depth inspection or are an obstacle to the proper performance of the inspection
  • minimizes disruption to the manufacturer's/CRO/QCL personnel and processes during the inspection and complies with any health and safety or other requirements of the manufacturer
  • assists the lead inspector in preparing the report of the inspection
  • assists the manufacturer/CRO/QCL to understand WHO prequalification requirements
  • when and where applicable provides input to verify that corrective actions that have been taken and have been or will be taken are likely to be effective.

The manufacturer, CRO or QCL

Following receipt of inspection observations verbally at the closing meeting, and thereafter of the inspection report, and if any observations were made, the manufacturer, CRO or QCL is responsible for:

  • performing both vertical and horizontal analysis of the issues raised as a result of any specific observations in order to assess the extent of the underlying deficiency, and any impact on other areas of manufacturing (in the case of a manufacturer) and control (in the case of a manufacturer or QCL), or on the different studies conducted (in the case of a CRO).
  • determining the root cause of all observations identified
  • determining the corrections and corrective actions to be taken to address the observations and to appropriately address directly-related, but also related systemic issues
  • submitting a corrective action plan within 30 days of receipt of the inspection report
  • implementing and verifying the effectiveness of the corrective actions in a timely manner
  • informing WHO of the completion of these actions as required
  • informing WHO of any subsequent significant change to the quality system (in the case of a manufacturer, CRO or QCL) or product(s) (in the case of a manufacturer).

If critical observations or a large number of major observations were made during the inspection and communicated at the closing meeting, and/or in the inspection report, the impact on products already released to market (in the case of a manufacturer), or on studies that were already performed (in the case of a CRO), should be assessed by all involved parties.

In the case of a manufacturer, timely and appropriate action should be taken for a product that has already been manufactured. This should include evaluating whether any product released to the market should be recalled.

In the case of a CRO inspection, the CRO concerned should communicate the inspection findings to the sponsor promptly. The sponsor of the relevant study(ies) performed at the CRO is expected to take appropriate action concerning the studies conducted. This may include withdrawing the data generated by a clinical study(ies) and submitted to WHO as part of a submission for prequalification of a product or products.

Clinical studies cannot be corrected retrospectively. So if submitted clinical data can no longer be considered reliable, a new study or studies, under conditions that comply with WHO Good Clinical Practices for Trials on Pharmaceutical Products and WHO Good Laboratory Practice, may have to be performed.

Standard of conduct

All members of the inspection team, and all observers and interpreters, must be made aware of and agree to meet the high standard of conduct expected during the entire inspection process (including pre- and post-inspection activities), maintain confidentiality and ensure absence of conflict of interest. The conduct required is in keeping with the requirements of the WHO and International Civil Service Commission Standards of Conduct for the International Civil Service.

 
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Dates and time allocated for inspection

The dates and time scheduled for an inspection are agreed upon by all participants under the guidance of the lead inspector and documented in an inspection plan.

In the case of a manufacturer, the dates proposed for the inspection should be during a time when:

the production line of the product undergoing prequalification assessment is active (if several products are inspected during the same inspection, the production line for at least one of them should be active)

quality control activities are being performed

key personnel for the quality management system, quality control and production line will be present.

In the case of a contract research organization (CRO), the dates proposed for the inspection will be based on the recommendation of the head of medicines assessment, and during a time when both the clinical and bioanalytical aspects of the study concerned can be covered.

In the case of a quality control laboratory (QCL), the dates for the inspection will be proposed after acceptance of the laboratory information file, and during a time when the QCL’s physico-chemical, instrumentation and microbiology sections can each be inspected.

The length of time allocated to the inspection will vary according to the complexity and scope of the inspection. (In the case of a manufacturing site, these will be influenced by the risks identified for both product and manufacturer.)

Once an inspection has been scheduled the manufacturer, CRO or QCL may be requested to provide an updated site manufacturing file, CRO master file or quality manual, as appropriate.

The inspection plan is usually provided one to two weeks before the inspection. It will:

  • define the inspection scope and purpose
  • confirm inspection team members
  • provide the date and place of inspection, and the expected time and duration of each inspection activity.

Language of on-site inspections

All inspections are conducted in English. To enable a smooth and effective inspection, the relevant higher-level quality management documents must be available in English. Translation and interpretation requirements, if any, are discussed with the manufacturer well ahead of the inspection itself.

Opening meeting

An opening meeting is held so that the inspection team and the team on-site can exchange information about the inspection process and site/study or quality control laboratory (QCL) to be inspected, as well as reconfirm the inspection scope, objectives and plan, and the availability of contact persons on site. The times indicated in tentative inspection plan may act as a guide. This meeting is normally restricted to one hour.

Expected outcomes of the inspection

An inspection of a manufacturing site seeks to confirm the adequacy and effectiveness of technical/production processes and that these are controlled effectively. The quality management system, including the effective implementation of the manufacturer's documented and validated procedures, is of critical importance and should be demonstrably robust.

Documents and records from all levels of the quality system will therefore be reviewed and inspectors will seek evidence of their appropriateness as well as their effective and consistent implementation Both formal and informal interviews of personnel at all levels and discussions with subject matter experts form an essential and major part of the inspection process.

Evidence of compliance and non-compliance will be collected on site through:

Additionally, evidence will be collected on site through:

  • examination of documents, including standard operating procedures and records
  • visual observation of activities
  • visual observation of environmental conditions
  • interviews to confirm statements of fact, before any observations are finalized.

Daily wrap-up meeting

Issues of potential concern identified during document review, and observations made during visual review of production and laboratory activities, or during interviews, will be notified as feedback, normally on a daily basis, at the meeting scheduled for the beginning of each inspection day.

The manufacturer/contract research organization (CRO)/QCL will be given an opportunity to comment on any observation made by the inspectors before it is finalized as an observation in the inspection report. But they should take the opportunity to correct any potential misunderstandings or matters of fact as they arise, and at the daily meetings.  An observation, even if corrected immediately, will be noted and form part of the final inspection report (with a note as to its correction).

Comments on issues of concern and on the performance of the inspection allow the manufacturer, CRO or QCL to demonstrate their understanding of any observation, to contest part, or all of the facts of the observation, or to provide additional clarification if necessary. If the manufacturer, CRO or QCL wishes to contest the observation, a rationale must be provided to support their view, including full supporting evidence.

Closing meeting

The closing meeting concludes the inspection and is held in the presence of the complete inspection team and the senior management team of the manufacturer/CRO/QCL. Other staff members may be invited by the senior management team, as appropriate.

The outcome of the inspection, including areas covered and not covered, limitations of the inspection, or the product/CRO/QCL will be presented. The lead inspector will summarize the inspection findings and issues of concern and present the list of observations. The inspectors will convey the provisional rating of the observations to indicate their order of importance with respect to implementation of corrective and preventive action (CAPA).

Inspection report

The inspection report will describe the main findings and any issues of concern,  and summarize the general outcome of the inspection. This will include listing of  observations that will require CAPA. Observations are classified as:

  • “critical” — i.e. there is potential risk of harm to the user of the product
  • “major” — i.e. major deviation from WHO Good Manufacturing Practices (GMP) has been observed
  • “other” — i.e. minor lapses or minor deviation from WHO GMP have/has been observed.

The target timeline for issuing of the inspection report by WHO is within 30 days of the on-site visit. If an inspection report cannot be issued within this time, the manufacturer, CRO or QCL will be notified of the delay.

Follow-up action by the manufacturer or QCL

If no observations were made during an inspection, the site or QCL inspected will be considered to comply with WHO requirements. But in most cases, some observations are made and will require action on the part of the manufacturer or QCL.

If none of the observations made them constitutes a critical or major observation, the site or QCL is deemed to have passed inspection. Nevertheless, it is expected that these minor observations will be attended to by those who have been inspected. If less than six major observations have been made, the site will normally be considered to be acceptable once satisfactory corrective and preventive actions (CAPAs) have been submitted and accepted by the inspection team. In the case of critical observations have been made, or a larger number of major observations, then the site will be considered to be operating at an unacceptable level of compliance with WHO requirements, and robust corrective measures and improvement will be expected. In such cases, CAPAs must be submitted and the site will normally require reinspection before a final decision is made on the acceptability of the site and CAPA effectiveness.

For each observation or nonconformity, the proposed CAPA must include:

  • root‒cause analysis and an assessment of risk and impact

  • correction if appropriate

  • corrective action to prevent recurrence

  • preventive measures where appropriate where the observation may have potential applicability elsewhere in the inspectees operations and procedures

  • timeline

  • responsibilities

  • a plan for evaluation of the effective implementation of the corrective action(s).

Inspections of the  manufacturing sites of active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs) are of four types:

  • initial
  • follow-up
  • routine surveillance
  • special (for cause).

Initial inspection

An initial or first inspection of an API or FPP manufacturing site is conducted only after the relevant API or FPP dossier has been accepted for assessment for prequalification. Such an inspection will be necessary if evidence from recent inspections conducted by other national medicines regulatory agencies operating to equivalent standards and stringency is insufficient. During the inspection, the site’s level of compliance with WHO Good Manufacturing Practices (GMP) will be assessed.

An API manufacturing site may be inspected as part of the assessment of an API for prequalification, or as part of the assessment of an FPP for prequalification.

If an initial inspection is considered necessary it will generally be scheduled within six months of acceptance for assessment of the relevant API or FPP, and announced one to two months before the inspection takes place. The procedure for an initial API or FPP manufacturing site inspection consists of:

  • review of the site master file submitted by the applicant at the time of dossier submission
  • review of product dossier for information of relevance to the inspection (such as information about the production process, sources of key starting materials, analytical methods, specifications, stability data, validation data), in preparation for on-site verification
  • inspection of the manufacturing site to assess compliance with WHO GMP
  • preparation and forwarding of the inspection report, listing all the observations and findings, to the applicant, within 30 days of the last day of the inspection
  • submission by the applicant, at the request of WHO, and within 30 days of receipt of the request, of no more than two rounds of proposed corrective and preventive actions (CAPAs), to correct deficiencies observed during the inspection
  • review by WHO of the proposed CAPAs, which may include a follow-up inspection ― within 6 months of the last day of the previous inspection if the written responses received are not considered adequate and especially if any “critical observations” were made during the inspection
    • if no "critical" and less than six "major observations" were made, the inspection can normally be closed out based on acceptance of the CAPAs; for "other" observations, CAPA implementation is confirmed during the next inspection, which will generally be a routine inspection
  • posting on this website of a WHO Public Inspection Report (WHOPIR) once the site is considered to comply with WHO GMP.

Follow-up inspection

In some instances, a follow-up inspection may be conducted to verify CAPA implementation by the manufacturer. It will normally be carried out within six months of the previous inspection (whether initial or routine).

The follow-up inspection of an API or FPP manufacturing site inspection consists of:

  • review of the submitted CAPAs and the report of their assessment
  • inspection of the manufacturing site to assess whether CAPA implementation is satisfactory
  • preparation and forwarding of the inspection report, listing all the observations and findings, to the applicant, within 30 days of the last day of the inspection
  • posting on this website of a WHO Public Inspection Report (WHOPIR) if the site is now considered to comply with WHO GMP.

Should the follow-up inspection reveal that CAPA implementation is unsatisfactory, the site must undergo and pass a further inspection if it is to attain be considered tto be in compliance with WHO GMP.

If the follow-up inspection is conducted after six months, it will be a full, routine inspection. That is, it will not be limited only to verification of the CAPAs that were requested by WHO in response to the previous inspection.

Routine surveillance inspection

Routine inspections of API or FPP sites that produce prequalified APIs or FPPs, or of API sites that produce APIs used in the manufacture of prequalified FPPs, are conducted to verify that the sites continue to comply with WHO GMP, and to monitor any trends of potential concern.

A routine inspection is scheduled between 12 and 36 months after the previous WHO inspection, and announced one to two months before the inspection takes place. Scheduling of routine inspections uses a risk-based approach: i.e. assessment of inspection need and frequency takes into account the complexity of manufacture of the dosage form, the level of compliance with WHO GMP previously observed, known changes (for example, relating to product range, variations, key personnel, equipment, premises) that that have been notified to WHO and/or have come to the attention of the inspection team since the previous inspection, and known quality issues as evidenced by product recalls or complaints, for example.

Routine inspection of an API or FPP manufacturing site consists of:

  • request for and review of an updated site master file
  • review of the previous inspection report and submitted CAPAs, and of any known changes (see above) or quality issues that have been notified to and/or have come to the attention of the inspection team since the previous inspection, in preparation for on-site verification
  • inspection of the manufacturing site to assess compliance with WHO GMP and, additionally, in some cases, that implementation of corrective and preventive actions (CAPAs) ― identified as necessary during an initial or earlier routine inspection ― was adequate
  • submission by the applicant, at the request of WHO, and within 30 days of receipt of this request, of no more than two rounds of proposed CAPAs, to correct deficiencies observed during the inspection
  • review by WHO of the proposed CAPAs, which may include a follow-up inspection ― within six months of the last day of the previous inspection ― if the written responses received are not considered adequate and especially if any “critical observations” were made during the inspection
    • if no "critical" and less than six “major observations” were made, the inspection can be closed out based on acceptance of the CAPAs; for “other" observations, CAPA implementation will be confirmed during the next inspection, which will generally be a routine inspection
  • posting on the this website of a WHO Public Inspection Report (WHOPIR) if the site has been confirmed as continuing to comply with WHO GMP.

Should routine inspection reveal that previous CAPA implementation was not satisfactory, or “critical” observations are made during the inspection, the site must undergo and pass a further inspection if it is to be considered as compliant with WHO GMP.

Special (for cause) inspection

A special inspection of an API or FPP manufacturing site may be scheduled in the event of:

  • receipt of information that manufacture at the site in question may no longer comply or no longer complies with WHO GMP
  • a stringent regulatory authority (SRA) has issued an alert about quality of manufacture at the site and/or about quality of products on the market that were manufactured at the site
  • complaints about the quality, safety, efficacy of a product or products manufactured at the site have been received from a procurer(s) or health care provider(s) or any member of the public.

A special inspection focuses on the specific causes (alert, complaint, etc.) that triggered the inspection and is generally scheduled at short notice.

A special inspection may be announced to the manufacturer, or, in the case of very serious concern, unannounced. Special inspections are very often planned together with SRAs who have registered product(s) manufactured at the site in question.

guidance Documents and Links

 

Inspections of contract research organizations (CROs) are of two types:

  • study-specific
  • special.

Study-specific inspection

A study-specific inspection may be undertaken if a CRO performed a clinical study(ies) for the finished pharmaceutical product (FPP) for which prequalification is sought. WHO may stipulate that the CRO be inspected to verify that the study(ies) comply(ied) with WHO Good Clinical Practices for Trials on Pharmaceutical Products (GCP) and WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies and to verify the data generated.

The decision as to whether or not to conduct an inspection of a CRO is taken using a risk-based approach, i.e. it takes into account the complexity of the relevant dosage form (e.g. with respect to solubility, polymorphism), the compliance status observed during previous WHO inspections and the corrective and preventive actions implemented, or inspections carried out by a stringent regulatory authority (SRA), and the date of any previous WHO or SRA inspections. CRO inspections are often triggered by WHO assessors' concern relating to data that is “too good to be true”, to the previous level of compliance of the CRO, or to the fact that the CRO is “new” to WHO.

A CRO inspection is generally scheduled with the CRO within six months of acceptance for assessment of the FPP dossier and announced one to two months before the inspection takes place.

A CRO inspection consists of:

  • review of the clinical and bioanalytical parts of the dossier submitted for the FPP concerned
  • request for and review of the CRO master file
  • inspection of the CRO to assess compliance with WHO GCP and WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies
  • preparation and forwarding of the inspection report, listing all the observations and findings, to the applicant, within 30 days of the last day of the inspection
  • submission by the applicant, at the request of WHO and within 30 days of receipt of this request, of no more than two rounds of proposed corrective and preventive actions (CAPAs), to correct deficiencies observed during the inspection
  • review by WHO of the proposed CAPAs
  • posting on this website of a WHO Public Inspection Report (WHOPIR) if the site is considered to have complied with WHO GCP and WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies during the study concerned.

If a CRO study-specific inspection determines that WHO GCP and WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies were not adhered to when the study was carried out, and therefore do not support the application for prequalification of the product concerned, the application may be rejected. Moreover, if “critical observations” relating to the overall compliance culture of the CRO and/or data integrity were made during the inspection, all previous studies conducted at this site — when linked to other any other applications for product prequalification — may also be rejected, unless they have been specifically inspected and found individually acceptable.

Special inspection

A special (investigational) inspection of a CRO may be scheduled in the event of:

  • receipt of information that the CRO may have made serious breaches of or does not adhere to WHO GCP and WHO Guidance for Organizations Performing In Vivo Bioequivalence Studies
  • an SRA has issued an alert about quality of the studies conducted by the CRO
  • complaints about the quality, safety, efficacy of a product or products for which the CRO has conducted a clinical study(ies) has/have been received from a procurer(s) or health care provider(s) or member(s) of the public.

A special inspection may be announced to the CRO, or, in the case of very serious concern, unannounced.

Inspections of quality control laboratories (QCLs) are of two types:

  • initial inspection
  • follow-up inspection
  • routine (surveillance) inspection.

Initial inspection

Initial or first inspection of a QCL is generally scheduled with the applicant within six months of acceptance of the QCL's laboratory information file (LIF) and quality manual, and announced one to two months before the inspection takes place.

An initial or first inspection of a QCL site consists of:

  • review of the LIF and the quality manual submitted by the applicant
  • inspection of the QCL to assess compliance with WHO Good Practices for Pharmaceutical Quality Control Laboratories (WHO GPQCL), WHO Good Practices for Pharmaceutical Microbiology Laboratories and relevant elements of WHO Good Manufacturing Practices (GMP)
  • preparation and forwarding of the inspection report, listing all the observations and findings, to the applicant, within 30 days of the last day of the inspection
  • submission by the applicant, at the request of WHO, and within 30 days of receipt of this request, of no more than two rounds of proposed corrective and preventive actions (CAPAs), to correct deficiencies observed during the inspection
  • review by WHO of the proposed CAPAs, which may include a follow-up inspection ― within six months of the last day of the previous inspection ― if the written responses received are not considered adequate and especially if any “critical” observations were made during the inspection
    • if no or less than six major observations were made, the inspection can be closed out based on acceptance of the CAPAs; for “other” observations, CAPA implementation is confirmed during the next inspection, which will generally be a routine inspection
  • posting on the this website of a WHO Public Inspection Report (WHOPIR) if the site is considered to comply with WHO GPQCL, WHO Good Practices for Pharmaceutical Microbiology Laboratories and relevant elements of WHO GMP.

Follow-up inspection

A follow-up inspection may be conducted to verify CAPA implementation by the QCL. It will normally be carried out within six months of the last inspection (whether initial or routine).

A routine QCL manufacturing site inspection consists of:

  • review of the submitted CAPAs and the report of their assessment
  • inspection of the site to assess whether compliance with WHO GPQCL, WHO Good Practices for Pharmaceutical Microbiology Laboratories and relevant elements of WHO GMP has been attained
  • preparation and forwarding of the inspection report, listing all the observations and findings, to the applicant, within 30 days of the last day of the inspection
  • posting on this website of a WHO public inspection report (WHOPIR) if the site now considered to comply with GPQCL, WHO Good Practices for Pharmaceutical Microbiology Laboratories and relevant elements of WHO GMP.

Should the follow-up inspection reveal that CAPA implementation has not been satisfactory, the QCL must undergo and pass a further inspection if it is to attain prequalification.

If the follow-up inspection is conducted after six months, it will be a full, routine inspection. That is, it will not be limited to verification of the CAPAs that were requested by WHO in follow up to the previous inspection.

Routine surveillance inspection

Routine inspection of a prequalified QCL is conducted to verify that that the QCL continues to comply with WHO GPQCL, WHO Good Practices for Pharmaceutical Microbiology Laboratories and WHO GMP.

Scheduling of routine inspections for QCLs uses a risk-based approach. This means that it takes into account the most recent inspection outcome (i.e. number of major and minor observations) if applicable, any complaints received from UN procurement agencies concerning the performance of the laboratory, the number of samples it has tested/failed, the number and type of out-of-specification results reported, changes in senior management, and any major, recent changes made in the laboratory pertaining to equipment, analytical methods or key personnel.

Routine inspections are scheduled between 18 months and 36 months after the previous WHO inspection, and one to two months before the inspection takes place.

A routine inspection of a prequalified QCL consists of:

  • review of the current LIF
  • review of the previous inspection report and CAPAs, and of known changes made to procedures, and of known quality issues that have arisen since the previous inspection, in preparation for on-site verification
  • inspection of the QCL to verify whether compliance with GPQCL, WHO Good Practices for Pharmaceutical Microbiology Laboratories and WHO GMP is being maintained and, additionally, in some cases, that implementation of corrective and preventive actions (CAPAs) ― identified as necessary during an initial or earlier routine inspection ― was adequate
  • preparation and forwarding of the inspection report, listing all the observations and findings, to the applicant, within 30 days of the last day of the inspection
  • submission by the applicant, at WHO's request, and within 30 days of receipt of this request, of no more than two rounds of proposed CAPAs, to correct deficiencies observed during the inspection
  • review by WHO of the proposed CAPAs, which may include a follow-up inspection ― within six months of the last day of the previous inspection ― if the written responses received are not considered adequate and especially if any “critical” observations were made during the inspection
    •   if no “critical” and less than six “major” observations” were made, the inspection can be closed out based on acceptance of the CAPAs; for “other” observations”, CAPA implementation will be confirmed during the next inspection, which will generally be a routine inspection
    • posting on this website of a WHO Public Inspection Report (WHOPIR) if the site has been reconfirmed as complying with GPQCL, WHO Good Practices for Pharmaceutical Microbiology Laboratories and relevant elements of WHO GMP.

Should routine inspection reveal that previous CAPA implementation was not satisfactory, or makes critical observations, the site must undergo and pass a further inspection if it is to be considered as compliant with GPQCL, WHO Good Practices for Pharmaceutical Microbiology Laboratories and relevant elements of WHO GMP. Additionally, the site may be suspended form the prequalified list or the scope of prequalification amended.

guidance Documents and Links

 

Where satisfactory recent, relevant and reliable evidence of compliance is available to WHO, an on-site inspection may be waived or deferred.

For active pharmaceutical ingredient (API) or finished pharmaceutical product (FPP) manufacturing sites

A waiver for inspection may be granted for an API and/or FPP manufacturing site if inspection by national medicines regulatory authorities (NMRAs) operating to equivalent standards and stringency has been performed within the past two years and a positive outcome declared. In such instances, WHO will conduct a desk review and decide whether a waiver of all or part of a site inspection can be given. During the desk review WHO will  review:

  • the inspection reports prepared by other NMRAs operating to equivalent standards and stringency
  • the extent to which the scope of that inspection was applicable to operations relevant to the product undergoing prequalification; this is especially important in relation to larger sites for which inspection coverage of operations for the product under prequalification may not have been adequate
  • implementation and proof of acceptable implementation of any corrective action and preventive actions relating to observations made during that inspection
  • an updated site master or laboratory information file
  • a copy of the manufacturing authorization
  • a list of all products manufactured on site
  • the most recent product quality review for the product(s) concerned
  • the batch manufacturing and packaging record for the product concerned
  • the list of any recalls that have occurred during the last three years
  • written confirmation from the senior quality assurance representative that a full self-inspection or external audit dedicated to the product has been performed within the preceding year.

For quality control laboratories (QCLs)

A waiver for inspection may be granted for a QCL following desk review of:

  • information on all inspections and audits performed during the past three years by external parties that apply standards that are at least equivalent to WHO-recommended quality standards for QCLs, related corrective and preventive action, and the final outcomes of those inspections or audits
  • a copy of the current authorization/license to conduct quality control testing
  • a list of all currently approved tests and/or expertise approved by the competent national authority
  • written confirmation from the senior quality assurance QCL representative that a full self-inspection has been performed within the preceding year
  • details of any complaints received from customers concerning the results of analysis performed by the laboratory
  • details of participation in any proficiency testing schemes (organizing party, methods involved, outcomes and, if appropriate, adopted corrective measures).
    GUIDANCE DOCUMENT

     

    It is WHO inspection policy to perform inspections, whenever and wherever possible, in collaboration with regulatory partners .

    WHO therefore invites national medicines regulatory authorities (NMRAs) of interested WHO Member States to participate in its inspections, be these of the manufacturing sites of active pharmaceutical ingredients or finished pharmaceutical products, or of contract research organizations, or of quality control laboratories.

    A collaborative procedure has been defined for this activity. It defines the objectives of joint inspections as:

    • optimizing use of WHO inspection resources
    • building the expertise and skills of inspectors from the NMRAs of low-income countries in particular
    • facilitating use of WHO inspection results within the national regulatory environment for information and decision-making.
    • facilitating international harmonization of inspection approaches and methods through joint inspections and sharing of outcomes.

    Any NMRA that is interested in participating in a WHO inspection should consult the Related Documents below.

    A request to participate in a WHO inspection, or for further information, should be sent to the head of the WHO prequalification inspection group.

    Related Documents and Links

    Documents

    Collaborative procedure between World Health Organization (WHO) and selected national medicines regulatory authorities (NMRAs) in inspection activities (16 January 2010)

    Collaborative procedure between World Health Organization (WHO) and selected national medicines regulatory authorities (NMRAs) in inspection activities (Annex B): Expression of interest (18 January 2010)

    Collaborative procedure between World Health Organization (WHO) and selected national medicines regulatory authorities (NMRAs) in inspection activities (Annex C): Shared inspection schedule (18 January 2010)

    Collaborative procedure between World Health Organization (WHO) and selected national medicines regulatory authorities (NMRAs) in inspection activities (Annex D): Form for nomination of an observer or co-inspector (18 January 2010)

    Collaborative procedure between World Health Organization (WHO) and selected national medicines regulatory authorities (NMRAs) in inspection activities (Annex E): Details of external expert (18 January 2010)

    Collaborative procedure between World Health Organization (WHO) and selected national medicines regulatory authorities (NMRAs) in inspection activities (Annex F): Provisions for evaluators of product dossiers and for inspectors (18 January 2010)

    Collaborative procedure between World Health Organization (WHO) and selected national medicines regulatory authorities (NMRAs) in inspection activities (Annex G): Appointment as an observer or co-inspector in a WHO inspection team: template letter (18 January 2010)

    Collaborative procedure between World Health Organization and selected national medicines regulatory authorities in inspection activities (Annex H): Appointment of observer or co-inspector: template letter to supervisor (18 January 2010)

     

    List of Guidance Documents Relating to Inspections

    Guidelines on prequalification procedures

    Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part (2012)

    Guidelines on submission of documentation for a multisource (generic) finished product. Preparation of product dossiers in common technical document format (2011)

    Guidelines on submission of documentation for prequalification of finished pharmaceutical products approved by stringent regulatory authorities (2014)

    Guidelines on submission of documentation for prequalification of innovator finished pharmaceutical products approved by stringent regulatory authorities (2011)

    Guidelines on variations to a prequalified product (2013)

    Procedure for assessing the acceptability, in principle, of active pharmaceutical ingredients for use in pharmaceutical products (2009)

    Procedure for prequalification of pharmaceutical products (2011)

    Guidelines on inspection practice

    Guidance on good data and record management practices (2016)

    Guidance on good manufacturing practices: inspection report (2016)

    Guidelines for inspection of drug distribution channels (1999)

    Guidelines on pre-approval inspections (2002)

    Model certificate of good manufacturing practices

    Provisional guidelines on the inspection of pharmaceutical manufacturers (1992)

    Quality system requirements for GMP inspectorates (2002)

    Guidelines on manufacturing practice

    Application of hazard analysis and critical control point (HACCP) methodology to pharmaceuticals (2003)

    Good manufacturing practices for active pharmaceutical ingredients (2010)

    Good manufacturing practices for biological products (2016)

    Good manufacturing practices for pharmaceutical products containing hazardous substances (2010)

    Good manufacturing practices for pharmaceutical products: main principles (2014)

    Good manufacturing practices for radiopharmaceutical products (2003)

    Good manufacturing practices for sterile pharmaceutical products (2011)

    Good manufacturing practices: supplementary guidelines for the manufacture of investigational pharmaceutical products for clinical trials in humans (1996)

    Good manufacturing practices: supplementary guidelines for the manufacture of pharmaceutical excipients (1999)

    Good manufacturing practices: water for pharmaceutical use (2012)

    Good manufacturing practices: active pharmaceutical ingredients (2010)

    Guidelines for drafting a site master file (2011)

    Guidelines on quality risk management (2013)

    Q&A: Heating, ventilation and air-conditioning systems  (1 November 2016)

    Recommendations for quality requirements when plant-derived artemisinin is used as a starting material in the production of antimalarial active pharmaceutical ingredients (2015)

    Supplementary guidelines on good manufacturing practices for heating, ventilation and air-conditioning systems for non-sterile pharmaceutical dosage forms (2011)

    Supplementary guidelines on good manufacturing practices: validation (2006)

    Guidelines for laboratories & contract research organizations

    Good practices for pharmaceutical quality control laboratories (2010)

    Good practices for pharmaceutical microbiology laboratories (2011)

    Guidance for organizations performing in vivo bioequivalence studies (2016)

    Guidance on the selection of comparator pharmaceutical products for equivalence assessment of interchangeable multisource (generic) products (2015)

    Guidelines for good clinical practice for trials on pharmaceutical products (1995)

    Guidelines for preparing contract research organization master file (2010)

    Guidelines on registration requirements to establish interchangeability (2015)

    Points to consider for inspections of biowaiver data (10 October September 2016)

    Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms (2006)

    To assist manufacturers in resource-limited countries who are keen to attain product prequalification, WHO-PQT is initiating a pilot collaboration whereby manufacturers can request verification of their compliance with WHO Good Manufacturing Principles (GMP) before they submit an application for WHO prequalification.

    This concept has already been tested successfully in cooperation with the Nigeria's National Agency for Food and Drug Administration and the Pharmaceutical Manufacturers Association of Nigeria.

    Guidance document

    Collaboration in verification of GMP compliance between WHO-PQT and medicines manufacturers interested in submitting an application for WHO prequalification (16 June 2016)

    Template

    Example of a development plan for submission of a medicinal product for prequalification (19 August 2016)

    Application form

    Request for pre-inspection (19 August 2016)