API Registration Process in Pakistan

The registration of Active Pharmaceutical Ingredients (APIs) in Pakistan is regulated by the Drug Regulatory Authority of Pakistan (also known as DRAP). In this article, we will give you an overview of the API registration process in Pakistan, starting with a brief introduction to regulatory framework, application procedures, and the roles of various stakeholders involved in the process. So, without further delay, let’s dive right into the article!

Introduction

Active Pharmaceutical Ingredients (APIs) are the biologically active components in pharmaceutical drugs responsible for producing the intended therapeutic effects. In API registration process, the efficacy, quality, and safety of APIs, along with many other factors, are assessed before market approval. In Pakistan, the registration of APIs is governed by the Drug Regulatory Authority of Pakistan (DRAP).

The API registration process in Pakistan differs from the registration of finished drug products. While both processes are overseen by DRAP, API registration focuses specifically on the active substances used in drug formulations, evaluating their quality, manufacturing processes, and compliance with Good Manufacturing Practices (GMP). In contrast, the drug product registration process undergoes a broader assessment, including the finished product's formulation, therapeutic efficacy, safety profile, and labeling.

Internationally, the approach to API and drug product registration varies from regions to regions based on applicable local regulatory requirements. However, many countries adopt the Common Technical Document (CTD) format, developed by the International Council for Harmonisation (ICH), to standardize the submission of information for the registration of pharmaceuticals. Pakistan too has adapted the CTD format for the registration of human pharmaceutical drug products, as indicated in DRAP's guidance documents.

Regulatory Framework in Pakistan

In Pakistan, the regulation of Active Pharmaceutical Ingredients (APIs) is governed by a comprehensive legal framework established through the Drug Regulatory Authority of Pakistan (DRAP) and some legislative acts.

Drug Regulatory Authority of Pakistan (DRAP)

Established under the Drug Regulatory Authority of Pakistan Act, 2012 (DRAP Act), DRAP serves as the autonomous body responsible for the regulation and enforcement of pharmaceutical standards across the country. DRAP was created to provide effective coordination and enforcement of The Drugs Act, 1976, and to harmonize inter-provincial trade and commerce of therapeutic goods. DRAP's mandate encompasses a wide range of functions, including the registration, licensing, and oversight of pharmaceuticals so that the therapeutic goods available in the market meet prescribed standards of quality, safety, and efficacy. DRAP operates under the administrative control of the Ministry of National Health Services, Regulations & Coordination.

Legal Provisions

The foundational legal instrument for drug regulation in Pakistan is the Drugs Act, 1976. It provides the legal provisions for regulating the import, export, manufacture, storage, distribution, and sale of drugs so that all pharmaceutical products meet defined standards of quality and are safe for consumer use.

Through the establishment of DRAP and the enactment of these legal provisions, Pakistan has developed a regulated approach to pharmaceutical regulation, with the sole purpose of protecting public health.

API Registration Process in Pakistan

The registration of Active Pharmaceutical Ingredients (APIs) in Pakistan is a structured process governed by the Drug Regulatory Authority of Pakistan (DRAP). The application process for API registration encompasses several steps. These are:

1. Preparation of Dossier

In the first step, applicants are required to compile a dossier adhering to the Common Technical Document (CTD) format, as mandated by DRAP. The CTD format standardizes the presentation of data and facilitates the evaluation process. The dossier consists of three main modules:

Module 1: Administrative Information

It includes:

o Details of the applicant and manufacturer, including name, address, and contact information.

o Application form (Form 5F) duly completed.

o Evidence of fee payment.

o Relevant certificates such as Good Manufacturing Practice (GMP) compliance.

Module 2: Quality Documentation (Chemical, Pharmaceutical, and Biological Documentation)

It includes:

o Comprehensive information on the API's nomenclature, structure, and general properties.

o Detailed description of the manufacturing process, including flow charts and controls.

o Specifications and analytical methods for the API.

o Stability data supporting the proposed retest period or shelf life.

Module 3: Non-Clinical and Clinical Data

It includes:

o Summaries of pharmacology, pharmacokinetics, and toxicology studies.

o Clinical study reports demonstrating the safety and efficacy of the API.

The detailed guidance on compiling the CTD dossier is available under DRAP's "Guidance Document for Submission of Application on CTD Format.

2. Submission of Application

Once the dossier is prepared, the application is submitted to DRAP using the prescribed application form. For APIs intended for human use, Form 5F is used. The submission must include all requisite documents and the applicable fee, as outlined in DRAP's application processes.

3. Evaluation Process

Upon receipt of application, DRAP thoroughly evaluates it to ensure the API's compliance with established standards. The evaluation process includes scientific review and site inspection.

In scientific review, the submitted data is assessed to evaluate the efficacy, quality, an safety of the API. It includes review of the manufacturing process, control measures, and robustness of the analytical methods used.

In site inspection, DRAP audits the manufacturing facility to check for compliance with GMP. In the inspection, all aspects related to GMP are assessed, including production, dispensing, raw material acquisition, warehouse, quality control, and quality management.

Once the evaluation process is complete, the evaluation findings are presented to DRAP's Registration Board, which deliberates on the approval or rejection of the application. The decision is based on the comprehensive review and inspection outcomes, ensuring that only APIs meeting the requisite standards are approved.

Post-Registration Obligations

The registration of an Active Pharmaceutical Ingredient (API) in Pakistan does not mark the end of regulatory compliance. Holders of an API registration must fulfill several post-registration obligations to ensure continued compliance with the Drug Regulatory Authority of Pakistan (DRAP) requirements. These include:

Renewal of Registration

API registrations are granted for a specified period, after which renewal is mandatory to maintain the registration’s validity. The key aspects of renewal process are:

•  Submission of a Renewal Application: The applicant must submit a formal renewal request before the registration expires. Delays in submission  of a renewal application may lead to the suspension or cancellation of the API’s approval.

•  Updated Documentation: Any changes or updates in documentation, such as stability data, manufacturing process updates, and any revisions in quality control procedures also require renewal of registration.

•  Renewal Fee Payment: A prescribed renewal fee must be paid as per DRAP’s schedule of charges.

•  Regulatory Review: DRAP assesses the updated dossier to confirm that the API continues to meet safety, efficacy, and quality standards.

Post-Registration Variations

Any significant modification to the API after registration requires prior approval from DRAP through a formal variation application. Some examples of common post-registration changes are:

•  Changes in Manufacturing Process: Adjustments in raw materials, production steps, or scale-up modifications must be justified with supporting data.

•  Change of Manufacturing Site: If production is moved to a new facility, DRAP must inspect and approve the new site for compliance with Good Manufacturing Practices (GMP).

•  Changes in Specifications or Analytical Methods: If new testing methods or quality parameters are introduced, the revised documentation must be submitted.

•  Labeling or Packaging Changes: Any updates to labeling information or packaging materials must comply with DRAP’s labeling regulations.

Challenges and Recommendations

The API registration process in Pakistan faces several challenges that can impact the pharmaceutical industry’s efficiency and competitiveness. Let’s review some of these challenges and how they can be addressed.

Regulatory Delays

One of the most significant hurdles in API registration is the prolonged approval timeline. Lengthy evaluation procedures, administrative bottlenecks, and resource constraints within the DRAP can delay the introduction of new APIs into the market, hindering pharmaceutical companies from bringing new drugs to production and impacting patient access to essential medicines.

However, these challenges can be addressed by updating the application review process using digital submission systems and fast-track pathways for priority APIs.

Dependence on Imports

Pakistan heavily relies on imported APIs, primarily from China and India, to meet its pharmaceutical production needs. This dependency on imports creates vulnerabilities, such as supply chain disruptions due to geopolitical issues, trade restrictions, or raw material shortages. What’s more, reliance on foreign sources limits the growth of the local pharmaceutical industry and exposes the market to fluctuating prices.

There are many ways these challenges can be addressed, such as:

•  Encouraging domestic API production through incentives such as tax exemptions, subsidies for local manufacturers, and relaxed regulatory pathways for homegrown APIs

• Developing industrial zones dedicated to API manufacturing, providing infrastructure and support services to facilitate local production.

• Strengthening collaborations between academia and the pharmaceutical industry to enhance R&D efforts in API synthesis.

Quality Assurance

Maintaining the quality of APIs remains a challenge for locally manufactured ingredients. Compliance with Good Manufacturing Practices (GMP) and international quality standards such as those of the International Council for Harmonization (ICH) is essential to maintain the safety and efficacy of pharmaceutical products. However, gaps in regulatory enforcement and a lack of technical expertise can lead to quality inconsistencies. Fortunately, this can be addressed by conducting frequent and rigorous GMP inspections to ensure that both local and imported APIs meet international quality standards.

Conclusion

The registration of APIs in Pakistan is a structured process regulated by DRAP and designed to ensure that pharmaceutical products meet stringent quality, safety, and efficacy standards. Therefore, stakeholders need to have a solid understanding of and adhere to DRAP's regulatory requirements so they can contribute to a pharmaceutical sector that safeguards public health.