The European Agency for the Evaluation of Medicinal Products
`Human Medicines Evaluation Unit
`
`London, April1996
`CPMP/QWP/486/95
`
`COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS
`(CPMP)
`
`NOTE FOR GUIDANCE ON
`MANUFACTURE OF THE FINISHED DOSAGE FORM
`
`Re-Issue*
`
`DISCUSSION IN THE QUALITY WORKING PARTY
`
`June 1995
`
`APPROVALBYTHECPMP
`
`DATE FOR COMING INTO OPERATION
`
`September 1995
`
`1 April1996
`
`*Note: Re-issue following clarification oftext and typographical corrections in Aprill996
`
`7 Westferry Circus, Canary Wharf, London E14 4HB, UK
`Switchboard: (+44-171) 418 84 00 Fax: (+44-171) 418 84 47
`E_Mail: mail@emea.eudra.org http://www.eudra.org/emea.html
`
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`MANUFACTURE OF THE FINISHED DOSAGE FORM
`
`Note for Guidance
`Concerning the application of Part 2, section B of the Annex to Directive 75/318/EEC,
`as amended by Directive 91/507/EEC,
`with a view to the granting of a marketing authorisation.
`[EMEA status as of April 1996]
`
`1.
`
`INTRODUCTION
`
`According to Directive 65/65/EEC, an application for a marketing authorisation shall contain a
`brief description of the method of preparation.
`
`This is described in more detail in the Annex, Part 2 of Directive 91/507/EEC, which states:
`
`"The description of the method of preparation [ ... ] shall be drafted in such a way as to give an
`adequate synopsis ofthe nature of the operations employed.
`
`For this purpose it shall include at least:
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`•
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`•
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`•
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`•
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`•
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`mention of the various stages of manufacture, so that an assessment can be made of
`whether the processes employed in producing the pharmaceutical form might have
`produced an adverse change in the constituents,
`
`in the case of continuous manufacture, full details concerning precautions taken to
`ensure the homogeneity of the finished product,
`
`the actual manufacturing formula, with the quantitative particulars of all the substances
`used, the quantities of the excipients, however, being given in approximate terms in so
`far as the pharmaceutical form makes this necessary; mention shall be made of any
`substances that may disappear in the course of manufacture; any overage shall be
`indicated and justified,
`
`a statement of the stages of manufacture at which sampling is carried out for in-process
`control tests, where other data in the documents supporting the application show such
`tests to be necessary for the quality control of the finished medicinal product,
`
`experimental studies validating the manufacturing process, where a non-standard method
`of manufacture is used or where it is critical for the product,
`
`for sterile products, details of the sterilisation processes and/or aseptic procedures
`used."
`
`This Note for Guidance provides guidance on the background and the interpretation of some
`aspects of the text of the Directive.
`
`This Note for Guidance does not pertain to biological medicinal products such as vaccines,
`sera, toxins and allergens, products derived from human blood and plasma as well as medicinal
`products prepared biotechnologically.
`
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`2.
`
`THE APPLICATION FOR MARKETING AUTHORISATION AND GMP
`
`Medicinal products on the market in the EC should be produced under the EC Rules for Good
`Manufacturing Practice (GMP), see Directive 91/356/EEC.
`
`Many general elements of GMP and quality assurance do not need to be described in the
`application for marketing authorisation. Examples are qualifications of key personnel, cleaning
`procedures for the production equipment and production areas, final packaging and labeling
`procedures etc.
`
`In general, the dossier for marketing authorisation should contain only those elements of the
`quality assurance which are specific for the medicinal product, whereas non product related
`elements of the quality assurance fall within the field of GMP, consequently, no description is
`necessary in the application for a marketing authorisation.
`
`This Note for Guidance addresses the items that should be presented in the application for a
`marketing authorisation. For items not to be covered by the application for a marketing
`authorisation, the obligation for adherence to the EC GMP principles is implicit.
`
`3. MANUFACTURING FORMULA
`
`The intended batch size should be indicated.
`
`An application for a variable and/or alternative batch size should be justified. Consistent
`conformity of the finished product to all the specifications should be made plausible.
`
`The names and quantities of all ingredients used in the course of the manufacture should be
`stated. This includes ingredients which are removed from the product during the production
`process, such as solvents. Substances that may not always be used should also be mentioned,
`such as acids and alkalis for pH adjustment. Overages must be indicated in quantitative terms
`and justified in the section on Development Pharmaceutics.
`
`For each ingredient, the allowed upper and lower acceptance limits for the actual quantity of
`each ingredient from the nominal quantity of the batch manufacturing formula should be
`stated.
`
`For active ingredients, these acceptance limits should be within 95 to 105% of the nominal
`quantity; for excipients, acceptance limits of 90 to 110% of the nominal quantity are
`acceptable without further justification.
`
`Wider acceptance limits may be acceptable but should be justified by showing that batches
`with a composition close to the upper and lower proposed acceptance limits remain within
`the finished product specifications.
`
`When that the quantity of an active ingredient to be used is calculated from the actual assay
`value of the batch of that active ingredient ("factorisation"), this has to be indicated. If another
`ingredient is used to keep the total mass per batch equal to the quantity provided for in the
`batch manufacturing formula, this should also be indicated.
`
`4.
`
`DESCRIPTION OF THE MANUFACTURING PROCESS
`
`A description of the manufacturing process should be given.
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`A proposal to allow alternative steps in the manufacturing process (for instance: two
`alternative sterilisation methods for the container) should be accompanied by evidence
`showing that all processes proposed will consistently produce a finished product in
`compliance with the specifications.
`
`If relevant (see below), the apparatus to be used has to be described. The in-process controls
`and corresponding acceptance limits need to be described as well, when relevant (see below).
`
`The various steps in the manufacturing process and corresponding in-process controls should
`also be shown in a flow-chart.
`
`The presented data on the manufacturing process, apparatus and in-process controls are
`binding for the future manufacturing of the medicinal product, unless authorisation for changes
`is given by the Competent Authority.
`
`It is in the interest of both the applicant and the regulatory authorities to avoid unnecessary
`applications for variations. Very detailed descriptions of the manufacturing process,
`apparatus and in-process controls should therefore be avoided.
`
`In selecting the necessary level of detail the following should be considered:
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`•
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`•
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`•
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`the testing at release of the finished product,
`
`the description ofthe manufacturing process and apparatus,
`
`the in-process controls and validated acceptance limits.
`
`Together these should provide a high degree of probability that each unit of every batch of the
`finished product, will be in conformity with the specifications.
`
`So, if the consistent quality of a medicinal product can be fully safeguarded by the "implicit"
`production under GMP and testing of the finished product at release, the description ofthe
`manufacturing process need not be comprehensive, and apparatus and in-process controls
`need not to be described.
`
`However, many quality parameters that are tested at release do not provide sufficient
`certainty of the quality of the whole batch from a statistical point of view, because the quality
`parameter may not necessarily be homogeneous within the batch.
`
`An example is the homogeneous distribution of the active ingredient in solid and semi-solid
`dosage forms, i.e. content uniformity. Testing at release alone does not provide sufficient
`certainty for the content uniformity of the whole batch from a statistical point of view.
`
`So, the apparatus to be used and the appropriate in-process controls (i.e. mixing time, mixing
`speed etc.) and the validated acceptance limits for these in-process controls (see below) must
`be proposed in the application file.
`
`Another example is sterilisation. For all sterilisation processes, appropriate in-process
`controls and their acceptance limits are to be described in the application file, see below.
`
`5. DESCRIPTION OF THE MANUFACTURING CHAIN
`
`An account shall be given of the sites at which each stage of the manufacturing and assembly
`operations takes place. Different manufacturing sites belonging to the same company shall be
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`mentioned as separate units. The company responsible for the final approval of the release of
`the product onto the market shall be specified.
`
`6. VALIDATION DATA OF THE MANUFACTURING PROCESS
`
`Validation studies that are used to identify critical steps in non-standard manufacturing
`processes are part of the Development Pharmaceutics, and should be described in Part liA of
`the application file.
`
`Examples are: new dosage forms, the manufacturing of liposomes, etc.
`
`Irrespective of these Development Pharmaceutical process validations, process Validation
`results of the actual production process must be described in Part liB if conformity to the
`finished product specifications cannot be guaranteed to an acceptable degree of statistical
`certainty by testing the finished product at release. This holds also for standard manufacturing
`processes.
`
`Examples are mixing, granulation and emulsifying processes of solid and semi-solid dosage
`forms and non-pharmacopoeial sterilisation procedures, see below.
`
`Process validation data obtained with closely related medicine products may be acceptable.
`
`Please note that notwithstanding a successful process validation, the quality parameters
`related to the validated process should be specified under the release specifications and end(cid:173)
`of-shelf-life specifications. For instance, sterility should always be specified at release and
`end-of-shelf-life, notwithstanding a successful validation of the sterilisation process. Also, the
`content uniformity of solid and semi-solid dosage forms should be specified in the release and
`end-of-shelf life specifications, notwithstanding a successful process validation with respect
`to homogeneity.
`It may be acceptable to refrain from the routine testing at release of such a specification
`("parametric release"), see the Note for Guidance "Specifications and Control Tests on the
`Finished Product". With respect to parametric release in relation to sterilisation, the text of the
`Ph. Bur. "Methods of preparation of sterile products" is to be observed.
`
`7.
`
`SPECIAL ITEMS
`
`7.1 Method of sterilisation
`
`The choice of the method of sterilisation should be justified under Development
`Pharmaceutics, Part liA.
`
`According to the text of the Ph. Bur.: "Methods of preparation of sterile products", terminal
`sterilisation in the final container is to be preferred. Refraining from terminal sterilisation in
`the final container should be justified in the application file.
`
`In Part liB the actual sterilisation process to be applied should be described.
`
`All sterilisation processes should be carried out according to the instructions of the Ph. Bur. In
`the application file, an explicit statement should be made that the instructions of the Ph. Bur.
`are followed.
`
`According to the Ph. Bur., all sterilisation procedures should be validated and be carried out
`under the EC GMP-rules. However, in the application file for marketing authorisation for
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`some sterilisation procedures no, or only limited validation data and data on the bioburden of
`the product prior to the sterilisation need to be presented, see below.
`
`In the case of terminal sterilisation in the final container by heat using a reference condition of
`the Ph. Eur., only the time and temperature of the cycle and the acceptance limits of the
`corresponding in-process controls need to be provided in the application file.
`So, this holds for sterilisation by saturated steam at a minimum of 121 oc for 15 min. and by
`dry heat at a minimum of 160 oc for at least 2 hours.
`In accordance with the Ph. Eur., these conditions should be met within all units. However, the
`validation data showing that all units are subjected to these conditions are normally not
`required in the application file. They may be requested by the competent authorities in certain
`circumstances.
`
`For terminal sterilisation cycles in the final container by heat with a time and/or temperature
`below the values of the reference conditions of the Ph. Eur., not only the acceptance limits for
`the in-process controls for time and temperature should be stated, but also the maximum
`acceptable bioburden before sterilisation.
`
`The results of the validation of the sterilisation cycle with regard to the effectiveness in terms
`of the Sterility Assurance Level (SAL) obtained should be presented in the application file.
`
`For sterilisation by filtration the maximum acceptable bioburden prior to the filtration must be
`stated in the application. In most situations NMT 10 CFU's/100 ml will be acceptable,
`depending on the volume to be filtered in relation to the diameter of the filter. If this
`requirement is not met, it is necessary to use a pre-filtration through a bacteria-retaining filter
`to obtain a sufficiently low bioburden.
`
`The type of bacteria-retentive filter, and its pore size should also be described in the
`application. Pore sizes of 0.22 flm or less are acceptable without further justification, in
`accordance with the Ph. Eur. A proposal to use a larger pore size in combination with an
`additional sterilisation step has to be validated and justified in the application file.
`
`Results of media filling fall within the field of GMP and need not be presented routinely in the
`application for marketing authorisation but may be requested by the competent authorities in
`certain circumstances.
`
`For sterilisation by gamma and electron radiation, see the Note for Guidance "The Use of
`Ionization Radiation in the Manufacture of Medicinal Products".
`
`For sterilisation by ethylene oxide, the provisions laid down in the Note for Guidance
`"Limitations to the use of Ethylene Oxide in the manufacture of medicinal products" should be
`followed, i.e. its use as a sterilisation method is only acceptable if no other method of
`sterilisation is available.
`
`The application for marketing authorisation should contain a description of the apparatus,
`quantitative data on the mixture of gases to be used, data on the bioburden prior to
`sterilisation, the time of exposure of the gas, the temperature and humidity prior to and during
`the sterilisation cycle, and the conditions for the removal of ethylene oxide. All these
`conditions should be monitored by suitable in-process controls that are to be described
`together with the acceptance limits for these in-process controls.
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`Results of the process validation should be presented to justify these acceptance limits for the
`in-process controls. The results should demonstrate both an acceptable assurance, of sterility
`and removal of ethylene oxide to an acceptable level.
`
`Limits ofNMT 1 ppm of ethylene oxide (if applicable, measured by means of a simulated use
`extraction method) and NMT 50 ppm of ethylene chlorhydrin (or any other halogenated
`ethylenehydrin) are acceptable without further justification, once sterilisation by ethylene
`oxide has been justified.
`
`Notwithstanding successful process validation, a limit for residual ethylene oxide, and the
`corresponding validated analytical method, should be included in the product release- and end(cid:173)
`of-shelf-life specifications.
`
`7.2 Re-processing of residual product
`
`Procedures for the re-processing of residual product of non-biological medicinal products fall
`within the field of GMP and need not to be described in the marketing authorisation dossier.
`
`7.3 Removal of solvents or gases
`
`If toxic gases or solvents are used in the manufacture of the finished product, release and end(cid:173)
`of-shelf-life specifications for maximum acceptable residues of these solvents or gases should
`be proposed for the product. A justification for the proposed limits can be presented if
`required in Part IIA, Part liB or liE of the file. Both toxicological and technological aspects
`should be discussed in this justification.
`
`Stages of the manufacturing process which affect the levels of such materials in the product
`should be controlled by in-process controls and the acceptance limits for these in-process
`controls should be validated. The results of these process validations should be presented in
`the application for marketing authorisation; see the paragraph in 7.1 above on ethylene oxide
`sterilisation.
`
`7.4 Cleaning of primary packaging material
`Washing procedures of the primary containers and closures normally fall within the field of
`GMP and are not needed routinely in the application for marketing authorisation but may, in
`certain circumstances, be requested by the Competent Authority.
`
`7.5 Sterilisation of primary packaging material
`
`Where applicable, the sterilisation procedure of the primary containers and closures should be
`described, and, when necessary, validated according to the paragraph on sterilisation.
`
`7.6 Production areas
`Details on the production area, i.e. specifications for the microbiological quality of the areas
`and freedom from particles in the air normally fall within in the field of GMP and are not
`needed routinely in the application for marketing authorisation but may,
`in certain
`circumstances, be requested by the Competent Authority.
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