Capítulo XI. Plan de Finanzas
2. Recomendaciones
The European legislation does not require mandatory rou- tine GMP inspections for active substance manufacturers. Re- sponsibility for using only active substances that have been manufactured in accordance with good manufacturing prac- tice is placed on the holders of a manufacturing authorization. Art. 111 Directive 2001/83/EC (Art. 80 Directive 2001/82/EC for veterinary medicinal products), however makes provision for GMP inspections of active substance manufacturing sites to be carried out at the request of the manufacturer itself. The request for the inspection should be made to the EEA com- petent authority where the site is located or, in case of sites located in third countries, to a competent authority where the active substance is used as a starting material in the man- ufacture of medicinal products. If this is not the case, any EEA authority can be approached. There is no guarantee that such a request will be fulfilled, as the competent authorities need to balance such requests with other priorities. It should also be borne in mind that an inspection does not replace the responsibility of the manufacturing authorization holder using the active substance in question as a starting material and will not be accepted alone as adequate assurance that the manufacturing authorization holder has fulfilled its respon- sibilities.
Manufacturing authorization holders sometimes con- fuse the role of inspectorates with their own obligations but nevertheless, when inspection reports or GMP certificates is- sued by EEA, MRA partners, or other recognized authorities are available; these can provide useful information to manu- facturing authorization holders. However, these alone cannot fulfill the statutory obligations of the manufacturing autho- rization holder or the requirements of section 5.25 of the GMP Guide, but the results of inspections, may be used together with other supporting information in a risk-based approach by the manufacturer in establishing priorities for its own au- dit program of active substance suppliers.
A GMP certificate is a certificate issued, following a GMP inspection, by the competent authority responsible for carrying out the inspection, to confirm the GMP compliance status of the inspected site. GMP certificates are site spe- cific, but can be restricted to particular activities depending on the scope of the inspection (e.g., manufacturing activi- ties related to a specific product). Directives 2001/82/EC and 2001/83/EC, as amended state that after every GMP inspec- tion, and within 90 days of the inspection, a GMP certificate shall be issued to a manufacturer, if the outcome of the in- spection shows that the manufacturer complies with GMP.
CMPs are product specific certificates, issued by the competent authority that granted the marketing authoriza- tion (EMEA issues CMPs on behalf of the European Com- mission for centrally authorized products), in the context of the WHO certification scheme on the quality of pharmaceu- tical products moving in international commerce, to confirm the marketing authorization status of the products. These certificates also confirm the GMP compliance status of the manufacturing site(s). CMPs are mainly used by companies
to support applications to export their pharmaceutical prod- ucts to countries with less developed regulatory systems.
CEPs are certificates issued by the European Direc- torate for the Quality of Medicines (EDQM) to confirm that a certain active substance is produced according to the re- quirements of the relevant monograph of the European Phar- macopoeia or of the monograph on TSE. CEPs can be used by companies when submitting an application for market- ing authorization, and replaces much of the documentation required for the active substance in the marketing authoriza- tion dossier. GMP inspections of active substance manufac- turers can be requested by EDQM in the context of the CEP certification scheme.
EMEA does not perform inspections; they are carried out on its behalf by the national competent authorities of the member states of the EEA, in connection with products under the centralized marketing authorization procedure. The com- petent authority responsible for carrying out the inspection issues the GMP certificate, or makes an entry of noncompli- ance into the EudraGMP Database.
The EDQM allows raw material manufacturers to sub- mit and secure approval for their active pharmaceutical in- gredients besides the approval of the finished products; such approvals are not available in the jurisdictions of the FDA. Given below is submission requirement that can be used by the manufacturers to audit for the quality of the API in those instances where such certificates and/or DMF are not available.
I. 2.3.S DRUG SUBSTANCE
A. 2.3.S.1 General Information
Use of the substance: Route(s) of administration, maximum daily
dose.
Commercialization history: Summarize the history based on the
table in application form.
Declarations: Summarize the declarations appended to the application form:
- Manufacture of the substance in accordance with ICH Q7A
GMP rules
- Commitment by the manufacturer to keep the proposed holder
informed of any changes to the documentation
- If applicable: manufacturer’s authorization for X to act as rep-
resentative
- Willingness to be inspected (holder, manufacturers)
- Nonuse/use of materials of human or animal origin in the
process
1. 2.3.S.1.1 Nomenclature
(a) Recommended International Nonproprietary name (INN) (b) Chemical name(s)
(c) Company or laboratory code
(d) Other nonproprietary name(s) (e.g., national name, USAN,
BAN)
(e) CAS No.: Molecular Formula MW 93
94 Handbook of Pharmaceutical Manufacturing Formulations: Liquid Products
2.3.S.1.2 General Properties
Give summarized data on
(a) Physical description (e.g., appearance, color, physical state. . .) (b) Physical form (e.g., polymorphic form, solvate, hydrate): to be
commented especially if requested as grade
(c) Solubility and other properties as necessary
(d) Particle size: for example, nonmicronized, micronized, or any
grade claimed as subtitle
2.3.S.2 Manufacture
2.3.S.2.1 Manufacturer(s) (Name, Manufacturer)
and Sites Involved in the Entire Process
Give the name, address, and responsibility of each manufac- turer, including contractors and manufacturer and each pro- posed production site or facility involved in manufacture.
2.3.S.2.2 Description of Manufacturing Process
and Process Controls
(a) Give a brief narrative step-by-step description of the manufac-
turing process(es) and provide reference to detailed description in the documentation. Confirm the maximum batch size
(b) If applicable, summarize alternate processes and give a short
explanation of their use
(c) Comment shortly on recovery of materials (solvents, reagents,
and mother liquor) together with reprocessing steps and give a brief justification
2.3.S.2.3 Control of Materials
(I) Starting material(s)
(a) Give summarized specifications (including impurities pro-
file) including their justification based on studies of carry- over.
NB: If starting material is obtained by fermentation or is from herbal origin, summarize the information related to the nature of this material.
(II) Reagents and solvents
Summarize the quality and controls of the materials (e.g., raw materials, solvents pure, and/or recovered, reagents, catalysts) used in the manufacture of the drug substance.
2.3.S.2.4 Controls of Critical Steps and Intermediates
Summary of the controls performed at critical steps of the manufacturing process and on intermediates, compare ana- lytical procedures used for intermediates and final substance.
2.3.S.2.5 Process Validation and/or Evaluation
For aseptic processing and sterilization, only give the sum- mary of process validation and/or evaluation studies.
Chemical Name Ph.Eur. Impurity Applicant’s Ph.Eur. Origin Levels Found LOD of the LOQ of the
Specifications Specifications Method Method
Solvent/Reagent/Catalyst Used in Step X/Y Applicant’s Limit ICH Class/Limit Levels (PPM) LOD of the LOQ of the
Method Method
2.3.S.3 Characterization
2.3.S.3.1 Impurities
(I) Related substances
(a) Fill in the following table identifying related substances,
their origin, and distinguishing between potential and ac- tual impurities and comparing with impurity section of the monograph
(b) Justify these specifications based on data observed for
impurities in relevant batches
(c) Discuss briefly about the suitability of the mono- graph to control the potential impurities present in
the substance (residual starting materials, reactants, and reagents etc.)
(d) Specific discussion on possible genotoxic impurities:
Give a brief discussion on impurities with potential geno- toxicity based on the requirements of the guideline
(II) Residual solvent(s)/reagent(s)/catalyst(s) (a) Fill in the following table
(b) Discuss briefly the basis for setting the specification
2.3.S.4 Control of the Drug Substance
2.3.S.4.1 Specification
Give a table summarizing the proposed specifications.
2.3.S.4.2 Analytical Procedures
(a) Summarize of the analytical procedures
2.3.S.4.3 Validation of Analytical Procedures
Give the summary of the validation information for any in-house tests and compare shortly with the method(s) de- scribed in the monograph (cross-validation).
2.3.S.4.4 Batch Analyses
(a) Give a short description of the batches: batch number, batch size
date, and site of production
(b) Summarize the results for relevant batches (according to spec-
ifications and showing equivalence of any alternative supplier, process etc.)
2.3.S.4.5 Justification of Specification
Justify the drug substance specification
2.3.S.5 Reference Standards or Materials
(a) Give the source of primary reference standards or reference
materials (e.g., Ph.Eur.) for final substance and its impurities where relevant
(b) Summarize characterization and evaluation of in-house
EDQM Certification 95
2.3.S.6 Container Closure System
(a) Describe shortly the container closure system(s) for the storage
and shipment of the drug substance, as it has to be mentioned on the CEP in case a retest period is requested (i.e.. in a clear and understandable manner)
(b) Summarize the specifications (description+ identification)
2.3.S.7 Stability
State retest period claimed for the substance and storage recommendations, if any.
2.3.S.7.1 Stability Summary and Conclusions
(a) Summarize accelerated and long-term testing (e.g., studies
conducted, protocols used, results obtained)
(b) Justify of the retest period claimed based on data available