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Good Manufacturing Practice

1. Introduction

This guidance is meant to help applicants to comply with good manufacturing practices (GMP) requirements, and prepare for an inspection.

Good manufacturing practice (GMP) represents the minimum standard that a manufacturer of medicines must adhere to in their production processes. GMP serves to ensure that the products manufactured are:

    1. Consistently of high-quality
    2. Appropriate to their intended use
    3. In compliance with the requirements of the marketing authorization or clinical trial authorization or product specification

Entities subject to compliance with good manufacturing practice (GMP) include:

    1. Holders of Manufacturing licenses
    2. Holders of blood establishment authorizations
    3. Non-Kenyan facilities contracted by Kenyan marketing authorization holders
    4. Overseas facilities holding or intending to hold Kenyan marketing authorization
    5. Quality Control Laboratory for Pharmaceutical Manufacturers

The Kenya Pharmacy and Poisons Board (PPB) conducts inspections to assess the adherence of manufacturing sites to GMP standards established by the World Health Organization. These inspections occur as part of the application process for a manufacturer licence and are periodically conducted based on risk assessments.  Overseas manufacturing sites are also subject to inspections.

For guidance Manufacturers intending to market products in Kenya are expected to submit the most recent site master file in the format and content prescribed by the World Health Organization https://www.who.int/publications/m/item/trs961-annex14

In cases where an organization manufactures both human and veterinary medicines using the same facility, the PPB may conduct inspections for both areas but evaluate GMP compliance exclusively for human medicines.

The PPB has issued comprehensive guidance notes titled “Guidance Notes for Establishing Pharmaceutical Product Manufacturing Facilities in Kenya” to provide further clarity and direction on this matter.

2. Setting up a pharmaceutical manufacturing facility

The PPB has issued comprehensive guidance notes titled “Guidance Notes for Establishing Pharmaceutical Product Manufacturing Facilities in Kenya” to provide further clarity and direction on this matter (click here to access the guidelines).

3. Types of inspection

3.1       Marketing Authorization-related GMP inspections

The PPB conducts product-related routine GMP inspections when evaluating an application for a Kenyan marketing authorization (click here to a access Kenyan GMP application). These inspections assess whether the manufacturer complies with GMP standards. Manufacturers of products are informed in advance about these inspections.

In some instances, inspections are conducted jointly with inspectors from East African medicines regulatory agencies, as part of East Africa Joint Inspections. Under this framework, member states collaborate by deploying GMP inspectors to jointly assess the compliance of manufacturing sites with GMP principles. These sites would have applied through the East African Community pathways for the joint GMP inspections and product joint assessment for marketing authorization in respective countries (click here to access EAC joint application portal).

3.2       For-cause inspections

The PPB may initiate inspections of manufacturing facilities following significant product quality related complaints or recalls and if it becomes aware of potential GMP violations through various channels, including:

    1. Reports from whistleblowers.
    2. Notifications from other PPB departments.
    3. Alerts from other regulatory authorities.

For-cause inspections, often referred to as triggered inspections or special inspections, may involve minimal or no advance notification to the parties involved.

3.3       Concise inspections

The PPB may conduct concise inspection for manufacturers with consistent records of compliance with GMP requirements through previous routine inspections. Concise inspection focus on specific GMP requirements selected as indicators of overall GMP performance.

3.4       Follow-up inspections

This are GMP inspections by the PPB undertaken to monitor the results of Corrective actions. They are undertaken after a specified period after the initial inspections depending on the nature of the defects and the depth and extent of inspection to be undertaken.

4. Risk-based approach to inspections

Every manufacturer is assigned a risk rating, and the Kenya Pharmacy and Poisons Board (PPB) prioritizes inspections for those with the highest risk ratings. Manufacturers are typically notified of upcoming inspections in advance. However, under the short-notice inspection program, the PPB may provide little or no advance notification.

During these inspections, GMP inspectors assess the systems employed in the manufacturing of medicines. Following a GMP inspection, the inspected site’s risk rating is determined based on the following factors:

    1. The site’s compliance report.
    2. Internal information related to previous inspection history.
    3. Organizational changes

Any upward revision of the risk rating is subject to peer review by a team of GMP inspectors before finalization. Manufacturers or any other inspected sites have the option to appeal the PPB risk rating, taking into consideration the risk rating report.

5. Complete a pre-inspection form

Before an inspection, the inspected site may be required to complete a GMP pre-inspection compliance report comprising the company’s biodata and the site’s compliance details. This is not applicable for a triggered or for-cause inspection, which may be notified on short notice.

When the completion of this form is necessary, the inspected site should submit the fully filled form in MS Word Document format to the email address provided by the Lead inspector.

6. Scheduling of manufacturers for GMP inspection

Inspection schedules of applications are developed every six months and allocated tentative dates and inspection teams based on;

    1. Type and purpose of inspection to be performed;
    2. Anticipated duration of inspection based on plant size: number of blocks, production lines and activities;
    3. Location of the site;
    4. Compliance history and risk rating of the site.

7. The process of GMP inspection

PPB inspectors conduct GMP inspections to assess compliance with WHO GMP guidelines (https://www.who.int/teams/health-product-and-policy-standards/standards-and-specifications/norms-and-standards-for-pharmaceuticals/guidelines/production) and any other internationally recognized GMP guidelines adopted by Kenya. The PPB has issued guidance on GMP (current page) to help applicants understand the Kenyan requirements for GMP

During the GMP inspection, the PPB inspection team will:

    1. Interview relevant personnel.
    2. Review pertinent documents.
    3. Conduct on-site visits.

Site visits may encompass any facility or process involved in the production of medicines, including:

    1. Manufacturing areas.
    2. Quality Control (QC) laboratories.
    3. Storage areas.
    4. Stability study sites.
    5. Utility areas.
    6. Returned goods areas.

The inspection team may request additional documentation and samples for testing during the inspection. They may also adjust the inspection’s focus if they suspect significant non-compliance.

In the closing meeting, the inspector will provide feedback, discuss any identified deficiencies, and establish timelines for corrective actions.

8. GMP reliance mechanism

The PPB has published a reliance guideline (click here to access reliance guideline) in order to leverage the GMP inspection and certification activities of other identified Medicines Regulatory Authorities (MRA) when assessing the compliance of overseas manufacturing facilities intending to obtain marketing authorization in Kenya. This mechanism reduces duplication of efforts, optimizes resources, and facilitates the global supply chain of pharmaceuticals and other regulated products.

The PPB may recognize the GMP compliance decisions of identified NRAs or determine compliance of a manufacturer through a desk review of stringent regulatory authority inspection reports and related documents in possible lieu of a PPB on-site inspection.

PPB also leverages inspection outputs already produced by WHO prequalification, under the WHO collaborative procedure for accelerated registration of prequalified finished pharmaceutical products.

9. Classification of GMP inspection deficiencies

Deficiencies found during inspections are classified at 3 levels as summarized below based on the assessed risk level and may vary depending on the nature of the products manufactured;

9.1 Critical deficiencies

A critical deficiency is an observation that has produced or which may result in a significant risk of producing, a product that is harmful to the user.

9.2 Major deficiency

A major deficiency is a non-critical observation that:

  1. has produced or may produce a product that does not comply with its marketing authorization (including variations);
  2. indicates a major deviation from the GMP guide;
  3. indicates a failure to carry out satisfactory procedures for the release of batches;
  4. indicates a failure of the person responsible for quality assurance/quality control to fulfil his or her duties;
  5. consists of several “minor” deficiencies, none of which on its own may be major, but which together may represent a major deficiency and should be explained and reported as such.

9.3 Minor

A deficiency which cannot be classified as either ‘critical’ or ‘major’ or there is not enough information to classify it as ‘critical’ or ‘major’ but which indicates a departure from good manufacturing practice.

10. Actions after GMP inspections

Following the closing meeting of the inspection, the PPB team will provide the company with either an exit report or a draft report that confirms any identified deficiencies.

The company is expected to respond to the inspector using the official email address provided by the inspector. The response should confirm the proposed corrective and preventive actions along with the specified timelines (referred to as the Corrective and Preventive Action Plan) for completing these actions.

Upon receiving the proposed Corrective and Preventive Action Plan, the inspector will review the company’s response. If the response is deemed acceptable, the inspected company will receive a GMP certificate along with the GMP inspection report.

However, an inadequate or unacceptable response may lead to escalated compliance measures if further requests for information are not satisfactory.

11. Guidance on responding to a post-inspection letter

11.1 Inspection Completion:

The GMP inspection fee paid to the PPB covers all expenses related to inspection preparation, reporting, and the conclusion of the inspection process. An inspection is considered “complete” when inspectors have assessed the responses from the inspected facility regarding the deficiencies outlined in the initial Inspection Report.

11.2 Additional Office-Based Inspection Fee:

The PPB does not impose an additional office-based inspection fee, even if inspectors need to invest extra time overseeing post-inspection activities. This can happen when critical deficiencies or significant non-compliance issues require inspectors to ensure the adequacy of the company’s Corrective and Preventive Actions (CAPA) as the company works towards compliance.

These post-inspection activities may include:

    1. Reviewing CAPA plans.
    2. Conducting impact assessments.
    3. Receiving periodic CAPA status updates.

While the PPB inspectorate encourages inspected companies to respond in a manner that expedites the decision-making process regarding compliance following the inspection, it’s essential to note that adhering to a specific format is not obligatory.

11.3 Inspection with Critical deficiencies

Critical deficiencies will be more complex, and responses may take different formats depending on the issues cited. Specific guidance is therefore not provided, but the general principles below apply.

11.4 An inspection with Major deficiencies

Companies should submit a tabular Corrective and Preventive Action (CAPA) plan in the format provided by the inspector. The table should include major deficiencies issued by the PPB in column 1, the Most Probable Root Cause identified by the company in column 2, and the company’s proposed CAPA with timelines in the last column.

11.5 Site Response

The initial response should be placed under the “Most Probable Root Cause” and “Proposed CAPA and Timelines” sections. To facilitate efficient use of time, the answer to the deficiencies is raised directly, clearly and succinctly in each column, preferably on the same Word document provided. Verbose responses with extraneous information may be returned without review, with a request to simplify.

Under “Most Probable Root Cause,” identify the root cause most likely responsible for the issue based on analysis and validation. This is the cause that, when addressed, is expected to prevent the issue from recurring. Once the most probable root cause is determined, develop corrective and preventive actions to address the issue and document under the Corrective and Preventive Action (CAPA) column.

Corrective Action addresses the immediate issue and prevents its recurrence, while Preventive Action implements measures to prevent similar issues in the future.

Subtitle this first set of responses as “initial response”

It’s crucial for the company to:

    1. Clearly state actions and deadlines (DDMMYYYY). If the response is a commitment to ‘review a system’, then it should state when the review will be complete and what will happen with the output of the review, the inspector may request that the output be provided.
    2. Choose appropriate timelines that are realistic (do not give extended times for simple actions).
    3. Consider broader review of systemic issues including other sites/sections/aspects in the organisation and do not just respond with a correction to the single identified point.
    4. If all similar areas have been reviewed to find other examples of the deficiency, but no others were found, this should clearly be stated and should include a description of how the system review was performed.
    5. Where timelines are long due to the complexity of the solution, but operations are continued, implement interim actions. These should be designed to protect the patient until the longer-term action is complete.
    6. Provide evidence only when specifically requested.
    7. Provide the company response in an editable Word document to allow the inspector to respond (if required).
    8. Hard copies are not required and will not be reviewed.
    9. Place second responses of the site directly below the PPB request for additional information. The site should choose a new colour for all sets of responses and reply underneath the further request.
    10. Maintain consistency in responses when providing additional information.
    11. Not change the previous response text when providing additional information or further response

11.6 PPB request for further information

  1. The inspector requiring further information from the inspected company may put the request directly below the point that they require information on for using a different colour. The whole record of all queries and responses will therefore be in a single document.
  2. The use of different colours for each set of responses allows each party to clearly identify which points require further response.

11.7 An inspection with Minor deficiencies

Initial Site Responses for deficiencies classed as ‘Minor’ follow the same format for Major responses as outlined above.

11.8 Inspector Comments

Inspector comments are not deficiencies. The site should respond to comments, even if it is just to acknowledge them. Inspected companies are required to communicate with the inspector(s) in advance if the timeline commitment is going to be missed.

The post-inspection compliance decisions are based on the acceptance of the remediation actions and their associated timescales for completion. The registered email can be used to notify of delays to commitment completion.

11.9 Compliance Management

Companies demonstrating poor compliance without reaching the threshold for regulatory action may undergo the compliance escalation process (compliance management process). In such cases, a re-inspection may be conducted to ensure the completion of actions in accordance with the agreed remediation program.

The objective of continuing the Compliance Management process post-inspection is to assist companies in achieving compliance before regulatory action becomes necessary.

Further deficiencies identified during the re-inspection are independently reviewed by a peer review team, and the final classification is confirmed in writing within 30 days. The timescale for addressing deficiencies is typically 30 days and will be specified in the post-inspection letter.

If the company’s remediation plan is still in progress, the original deficiencies leading to compliance management escalation remain valid for consideration until it is confirmed that effective remedial actions have been implemented, usually upon re-inspection.

Companies are notified of compliance management objectives, which can be clarified by the inspector upon request.

Re-inspection deficiencies are reviewed by the peer review team, and further correspondence regarding continuing compliance action is communicated separately by the GMP department. This communication may follow the receipt and assessment of the company’s post-inspection responses.

Ongoing compliance management review determines whether there are grounds for the Licensing department to consider formal regulatory action, which may be based on current inspection deficiencies, inadequacy of proposals to correct these deficiencies, or failure to implement commitments effectively or promptly.

It is crucial for the company to maintain open communication channels with the assigned site inspector (the Senior Superintended Inspector) and the GMP department throughout the process. Any significant changes in GMP compliance, whether positive or negative, including delays in implementing corrective action commitments, should be promptly reported.

Once the compliance escalation process is concluded, the company returns to the routine risk-based inspection program. However, regulatory action may still be considered if the necessary improvements are not made.

The compliance escalation process may also be employed if the GMP peer review team has closed the referred case with a recommendation for monitoring until remedial action plans are completed.

This process may involve making recommendations for close monitoring of compliance improvement work through inspection, holding meetings and correspondence with company senior management to outline the consequences of continued non-compliance, and more.

12. Suspension of manufacturing licence

In cases where a manufacturer’s previous inspection has revealed critical and/or major deficiencies or when previously agreed-upon action plans to address inspection deficiencies remain unresolved, the Deputy Director of Inspectorate and Surveillance will take the following steps:

Increased Inspection Visits: The Deputy Director may initiate more frequent inspection visits to the facility in question.

Meeting with License Holder: The Deputy Director may request a meeting with the license holder to discuss the identified issues.

Recommendation for License Suspension: In severe cases, the Deputy Director may recommend to the Deputy Director of Licensing that the company’s manufacturing license be suspended.

If the company’s remediation plan is still in progress, the original deficiencies that led to the referral to the Licensing department continue to be valid for considering regulatory action until effective remedial actions are confirmed, typically upon re-inspection.

Manufacturers will have received prior notifications regarding potential regulatory actions and their implications. Any questions or clarifications regarding these actions can be addressed by the inspector or the Licensing department upon request.

It’s important to note that any actions taken will carefully consider the potential impact on the supply chain, particularly for medically critical products (those without available therapeutic alternatives). Should regulatory actions be restricted to maintain the supply of medically critical products, the PPB will notify the involved parties through subsequent correspondence.

The suspension of manufacturing licenses and other regulatory restrictions are not permanent barriers to manufacturing activities. These restrictions will be lifted if the manufacturer can demonstrate, usually upon re-inspection, the effective implementation of corrective actions that address the identified GMP deficiencies.

13. Key Personnel

14. Fees for GMP inspections

GMP for Foreign is USD4000

GMP for Local is USD1000

15. Contact

For further information on good manufacturing practices and for planning of GMP inspections, please email gmp@pharmacyboardkenya.org