Provisions for Contract Manufacturing of Finished Pharmaceutical Products
In Nigeria, members of the general public and especially organizations intending to engage in the manufacture of finished pharmaceutical products via contract manufacturing arrangements are expected to comply with a set of regulatory requirements put in place by the relevant agencies.
These regulatory requirements, put in place by the National Agency For Food and Drug Administration and Control (NAFDAC) and effective since the 3rd of February 2021, will be the focus of this article .
What are the implications of the NAFDAC Guidelines on Contract Manufacturing Of Finished Pharmaceutical Products in Nigeria?
The implications of the NAFDAC are that :-
– No regulated product should be manufactured, imported, exported, advertised, sold or distributed in Nigeria unless it has been registered in accordance with the provisions of the Food, Drugs and Related Products Act and accompanying guidelines.
– A drug product should not be manufactured in Nigeria unless the facility has been inspected, found to comply with good manufacturing practices and an authority to manufacture pharmaceutical products is issued by NAFDAC.
– The NAFDAC Guidelines prescribe the minimum requirements to be met by parties wishing to engage in contract manufacturing of pharmaceutical products i.e. human & veterinary medicines, biologics, herbal medicine and nutraceuticals as well as medical devices
What are definitions of terms most commonly used by the guidelines?
The definitions of terms most commonly used in the guidelines are as follows :-
– Contract Facility :- A site where one or more manufacturing operations take place on behalf of the contract giver.
– Contract Giver :- A legal entity who has legal ownership of the finished product and who will be applying to NAFDAC for marketing authorization or entity that orders the conduct of a component of manufacturing to be carried out on their behalf by another entity.
– Contract Manufacturer/Contract Acceptor :- An entity that engages in GMP activities, including implementation of oversight and controls over the manufacture of drugs to ensure quality of other parties.
– Contract Manufacturing :- Manufacturing by a contract manufacturer/contract acceptor on behalf of the contract giver.
– Good Manufacturing Practice(GMP) :- That part of quality assurance which ensures that pharmaceutical products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by their marketing authorizations. It ensures that pharmaceutical products are manufactured so that they do not place the populace at risk.
– Manufacturing :- Includes processing, packaging, holding, labeling operations, testing and quality unit operations.
– Quality Agreement :- A comprehensive written agreement between parties involved in the contract manufacturing of pharmaceutical products that defines and establishes each party’s manufacturing activities in terms of how each will comply with GMP.
What are the principles guiding contract manufacturing agreements?
Some of these principles include the following :
– A manufacturer may perform all operations and activities or may engage an outside party or parties to perform some or all of the operations and activities under contract. NAFDAC shall allow product owners/manufacturers to contract some of these operations to any contract facility as defined above.
– Contract production and any other activity covered by GMP that is outsourced must be correctly defined, agreed and controlled in order to avoid misunderstandings that could result in a product or work or analysis of unsatisfactory quality.
– All arrangements for contract manufacturing including technology transfer and any proposed changes in technical or other arrangements, should be in accordance with the marketing authorization for the product concerned.
– Contract manufacturing may be undertaken only by a manufacturer who holds a valid manufacturing authorization.
What are the types of contract facilities under these guidelines?
The NAFDAC has classified contract manufacturing facilities into 2 groups for proper definition of the scope of operations and effective regulation as follows :-
– Full Contract Manufacturing Facilities (FCMF) : These are establishments that do not have any product registered by NAFDAC and are only involved in contract manufacturing operations for other parties.
– Partial Contract Manufacturing Facilities (PCMF) : These are establishments that are holders of market authorizations issued by NAFDAC for manufactured and are also involved in commercial contract manufacturing operations for other parties.
What are the responsibilities of parties involved in contract manufacturing under the guidelines?
Contract Manufacturing Parties
– Each party engaged in the manufacture of a drug is responsible for ensuring compliance with GMP for the manufacturing activities it performs.
– The responsible person designated by the contract giver should be party to approving or rejecting pharmaceuticals products manufactured by the contract facility, including final release except if such responsibility is otherwise established in the quality agreement.
Contract Giver
– The Pharmaceutical Quality System (PQS) of the contract giver should be include the control and review of any outsourced activities.
– The contract giver is responsible for :-
a). Assessing the legality, suitability and competence of the contract acceptor to successfully carry out the work or tests required.
b). Approval for contract activities
c). Ensuring by means of the contract that the principles of GMP incorporating QRM principles are followed to include the implementation of oversight and controls over the manufacture of pharmaceuticals to ensure quality & management of risk.
Contract Manufacturer/Acceptor
– The contract acceptor must have adequate premises, equipment, knowledge, experience and competent personnel to satisfactorily carry out the work ordered by the contract giver.
– The contract acceptor should ensure that all products or materials delivered to the facility are suitable for manufacturing of finished pharmaceutical products.
The Contract
– All arrangements for production and analysis must be in accordance with the marketing authorization and agreed by both parties.
What are the considerations required by the guidelines in documenting GMP activities in quality agreements?
– A quality agreement describes the contract giver’s and the contract acceptor’s roles and manufacturing activities under GMP.
– A well-written quality agreement should use clear language, define key manufacturing roles and responsibilities and establishes expectations for communication and providing key contracts for both parties.
– It will specify which products and/or services the contract giver expects from the contact acceptor and who has final approval for various activities.
– Quality agreements should state manufacturing services provided by contract facilities will comply with GMP.
Guidelines For The Importation of Active Pharmaceutical Ingredients (APIs) in Nigeria
The Guidelines for the importation of Active Pharmaceutical Ingredients (APIs) as released by the National Agency For Food and Drug Administration and Control (NAFDAC) is intended to provide guidance on the process for obtaining permits for Active Pharmaceutical Ingredients (APIs) by Importers, Distributors, Brokers, Marketing Authorization Holders (MAH) who import or act as site for physical importation of APIs for own use or distribution, re-labellers, re-packers and other end users (e.g. educational, health and research institutions) in Nigeria.
This document is also intended to provide guidance for the control of APIs locally manufactured and distributed or exported out of the country.
API should not be imported into Nigeria unless the Finished Pharmaceutical Products (FPP) manufacturers, marketers, re-labelers, re-packers and other end users (e.g. Educational, health and research institutions) has been duly issued a Permit or Authorization to do so.
What are the definitions and abbreviations of important terms under the guidelines?
API(s) – Active Pharmaceutical Ingredient(s)
CTD – Common Technical Document
DS – Drug Substance
ASMF (DMF) – Active Substance Master File (Drug Master File)
LOA – Letter of Access / Authorization
FPP – Finished Pharmaceutical Product
MA – Marketing Authorization
MAH – Marketing Authorization Holder
Active Pharmaceutical Ingredient (API) or Drug Substance (DS)
– A substance used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings.
Drug Master File (DMF)/Active Substance Master File (ASMF)
-A document containing complete information of an Active Pharmaceutical Ingredient or finished drug dosage form. The drug manufacturer must include adequate information or data to demonstrate that the drug substance used for particular drug of interest will not in any way affect the safety and efficacy of the drug. The DMF contains complete and factual information on drug product chemistry, manufacture, stability, purity, impurity profile, packaging and the GMP of any human drug product. Drug Master Files consist of two parts namely open and closed parts.
What is the scope of these guidelines?
These guidelines apply to the following:
-All Drug Substances (DS) or Active Pharmaceutical Ingredients (APIs) that fall within the definition of APIs as given in this document whether manufactured locally, imported, exported, marketed, repackaged, relabeled, distributed, sold or used in the manufacture of drug products, for new products or generics in Nigeria except those materials indicated under exemption from these guidelines.
-Local manufacturers of Finished Pharmaceutical Products (FPPs) in Nigeria authorized by the Agency and intending to import APIs for manufacture of their products.
-Applicants who import APIs solely for the purpose of sale and distribution.
-Applicants who hold wholesale authorization for distribution and sale of APIs but are not direct importers of APIs (DMF not required).
-Applicants who are manufacturers of APIs (local or foreign) that export, distribute or import APIs into Nigeria.
-Applicants or Institutions who import APIs for the purpose of Research and Development (R&D).
-Brokers who import APIs for clients.
What is the application method for API Importation permits under the Guidelines?
Applicants regarded as API manufacturers, FPP manufacturers, MAHs, Importers, Brokers, Exporters, Educational, Research or Health institutions; should submit DMF or equivalent documentation for API(s) for which permit is sought either for the purpose of distribution or to be used in the manufacture of or research into:-
-Investigational medicinal products
-New drug applications
– Abbreviated new drug applications
– Variation, Supplements or amendments to any of the above
What are the exemptions to these guidelines?
-The requirements of these guidelines do not cover the following groups of materials:
- Biotechnology or biological active substances
- Immunological active substances
- Intermediates from process of APIs manufacturing
- Starting materials for APIs.
What is the application procedure for the issuance of permits for APIs?
The procedure for the control and issuance of permit for APIs is based on the following principles:
-Understanding of the production and quality control for the manufacturer of the API
-Assessment of API data and information including changes and variation submitted by the API manufacturer/Applicant
-Assessment of manufacturing site(s) for compliance with GMP requirements for APIs
-Post marketing surveillance through randomized sampling and testing of APIs
-Handling complaints and recalls
-Local and external monitoring of co-agencies on complaints
What are the requirements for the documentation for Importation of APIs?
All applications for API import permit should be made through the Federal Government through the Single Trade Portal.
The following documents to support the application should be submitted through the Federal Government Single Trade E-Portal:
-An application (prepared by legal counsel) for permit to import drug substance(s) or Active Pharmaceutical Ingredient(s) should be made on the company’s letter-headed paper, signed by the Managing Director of the company or designated technical officer and addressed to: The Director-General, National Agency for Food and Drug Administration and Control (NAFDAC).
-The application letter should indicate the applicant’s address, location address of API source, the list of APIs and the purpose for which the API is required
– importation, distribution, sale, manufacturing of FPP etc.
-Separate application letters should be submitted for different sites or sources of APIs.
– Applicants should duly complete an API request e-form on the portal under section of trader/client module to indicate the name of API and source of import (name and site address of API manufacturer), API grade e.g. USP or BP., size of unit pack e.g. 25kg bag, total amount requested in Kilogram (KG) per API, commodity code number as specified by the Nigeria Customs Service.
– An API manufactured from different sites, or with different synthesis route or of different salts should be treated as separate item when entering the list of APIs in the request form.
-The DMF (open and closed parts) or equivalent documentation (e.g. Common Technical Document modules 1 and 3) from the API Manufacturer(s) should be provided. This can be scanned and uploaded as an attachment to the application.
– The file size limit for scanned documents is 2 MB but there is no limit for the total size of all attachments. The file-size of an attachment can be reduced by scanning it in black and white instead of grayscale and with a scanning resolution of maximum of 300dpi.
– Note that as a result of file size limitation for scanned document attachments, DMFs (labeled) can also be submitted in a USB flash drive to NAFDAC.
-Current GMP Certificate or evidence of GMP compliance of the actual site of API manufacture and shipment to the applicant.
Inspection
– For FPP manufacturers and non-manufacturing importers, a risk-based approach is applied for GMP inspection of the FPP manufacturing site and importer’s warehouse respectively, and this will be done following successful assessment of DMF or equivalent documentation and payment of inspection fee.
-The modalities for inspection of the manufacturing site will be communicated to the applicant and a satisfactory report of such inspection or risk assessment in lieu of site inspection will be uploaded by NAFDAC inspectors on the e-portal for further processing of the application.
Approval
-A permit which authorizes the applicant to import the API is issued after a satisfactory review of DMF or equivalent documentation, satisfactory inspection of the manufacturing plant/warehouse and payment of appropriate API import permit fee.
What are the documentary requirements for an application for Permit to Import API by Educational, Research or Health Institutions?
The following documents are to be submitted online by other applicants (Educational, Research and Health Institutions) through the Federal Government Single Trade E-Portal:
-Covering letter signed by head of institution
-Duly completed online API application e-form
-Certificate of Analysis of API from manufacturer
-Evidence of payment for API Import Permit
– A letter of undertaking stating that the API is strictly for academic or research purposes.
-API importation by this set of applicants should not exceed 25kg per item .
– Importation of APIs by educational, research and health institutions may not require site audit or ASMF assessment.
-However, applicants in this category must pay the appropriate fees.
What do the guidelines say about post approval requests?
– Upon an initial approval, an applicant may request for additional APIs or additional quantities of approved items by following all the steps enumerated for processing a new application.
-DMF/ASMF submission will be required for additional items but not for additional quantities of approved items.
It should be noted that all approved API import permits must be utilized within the same calendar year of issuance.and neither constitutes legal advice nor a valid lawyer/client relationship.
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