Federal Register I Vol. 56. No. ‘I98 I Friday. October 11. -1991 I Proposed Rules
`51354
`
`Correction to NPRM
`
`Accordingly. pursuant to the authority
`delegated to me. the MDDRESSES section
`of the NPRM [Federal Register
`Document No. 91-22298]. as published
`on September 17. 1991 (58 FR 47038]. is
`corrected to read as follows:
`In the ADDRESSES section (page 47038.
`column 2]. starting on line eighteen.
`remove the words "]Fl( International
`Airport. Fitzgerald Federal Building.
`Jamaica. NY 11430" and add the words 1
`"R0. Box 20636. Atlanta. GA 30320."
`
`Issued in Washington. DC. on October at.
`1991.
`Hamid W. Becker.
`
`Manager. Airspocefluics andflerosnufical
`infonnorforr Dt'vfst’on.
`{FR Doc. 91-24582 Filed 1D*‘l0—9]: 8:45 am]
`BILLING CODE 4910-I3-II
`
`DEPARTMENT or HEALTH AND
`HUMAN seavlces
`
`Food and Drug Administration
`
`21 OFF! Parts 211. 314. and 514
`
`[Docket No. sin-son]
`
`HIN 0905 AD45
`
`Use of Aseptic Processing and
`Terminal Sterilization tn the
`Preparation ot Sterile Pharmaceuticals
`for Human and Veterinary Use
`
`AGENCY: Food and Drug Administration.
`HHS.
`
`ACTION: Proposed rule.
`
`seminar: The Food and Drug
`Administration [FDA] is proposing to
`amend the current good manufacturing
`practice [CGMP] regulations for human
`and veterinary drug products to require
`manufacturers to use a terminal
`sterilization process when preparing a
`sterile drug product unless such a
`process adversely affects the drug
`product. The proposal would also
`amend the regulations governing the
`approval for marketing of new drugs
`and antibiotics for human use and new
`animal drugs to require applicants to
`include in their marketing applications a
`written justification with supporting
`data when terminal sterilization is not
`used to prepare a sterile drug product.
`I-‘DA believes these actions will provide
`the highest possible assurance of
`sterility for drug products intended to be
`sterile.
`
`DATES: Written comments by December
`10. 1991. FDA proposes that any final
`rule based on this proposal be effective
`18 months after its date of publication in
`the Federal Register.
`
`Aoonssses: Written comments to the
`Dockets Management Branch [HFA—
`305). Food and Drug Administration. rm.
`1-23. 12420 Parklawn Dr.. Rockville. MD
`20357.
`FOR FURTHER INFORMATION CONTACT:
`
`Marilyn L. Watson. Center for Drug
`Evaluation and Research [HFD—.'i60).
`Food and Drug Administration. 5600
`Fishers Lane. Rockville. MD 20857. 301--
`295-8033.
`SUPPLEMENTARY INFORHATION:
`
`I. Introduction
`
`There are two principal processes for
`the preparation of sterile drug products.
`Aseptic processing involves the filling or
`assembly of presterilized drug products
`under aseptic conditions into
`presterilized containers. The drug
`product and its container and closure
`are sterilized separately. and the
`sterilization methods may differ
`depending upon the physical
`characteristics of the product and the
`container and closure. For example.
`liquid dosage forms are usually
`sterilized through filtration. Glass
`containers are often sterilized using dry
`heat: rubber closures are sterilized using
`pressurized steam: and plastic
`components may be sterilized using
`ethylene oxide or radiation. The
`sterilized drug product and sterilized
`container and closure are then
`assembled in a controlled environment.
`The filled container is seldom subjected
`to any further sterilization process but is
`sealed and labeled as being sterile. The
`many manipulations of the separately
`sterilized components during the
`assembly of the final drug product and
`the absence of a final sterilization
`process after the drug product has been
`sealed in its final container limit the
`degree of sterility assurance that can be
`attained. Careful control and validation
`of all operational phases of aseptic
`processing is imperative to achieve the
`highest possible degree of sterility
`assurance. The failure to satisfactorily
`process any component of the drug
`product or the product's container and
`closure could result in contamination of
`the other sterile components of the drug
`product.
`In contrast. terminal sterilization is a
`_ process whereby a drug product. which
`may or may not be presterilized. is filled
`and sealed in a container and then
`subjected to final sterilization. The
`sterilization method is usually
`autoclaving. a process that can virtually
`eliminate the possibility of
`contamination if properly validated and
`carried out. Radiation is another method
`of terminal sterilization. With terminal
`sterilization of the final product. the
`
`possibility -of poststerilization.
`contamination of the drug product is
`usually due to a breach of container-
`closure integrity.
`The principal difference between
`aseptic processing and terminal
`sterilization ofs drug product in the
`degree of confidence regarding the .
`assurance of sterility is most notably
`reflected in the statistical probability of
`the existence ofa nonsterile unit in a lot
`
`or batch. A properly conducted and _
`validated terminal sterilization process
`will achieve a degree of sterility
`assurance such that there will be less
`than one chance in a million11o.“) that
`viable microorganisms are present in
`any final product container. in contrast.
`current aseptic processing methods.
`even when performed under optimal
`conditions. can only be validated to
`ensure that the contamination rate is no
`greater than ‘I Conlamina ted unit per
`1,000 {10"} filled. In practical terms.
`these statistical probabilities mean that.
`for a drug product sterilized by a
`properly controlled and validated
`terminal sterilization process with an
`uncompromised container-closure
`system. there is virtually no chance of
`microbiological contamination of the
`drug product. For a sterile drug product
`prepared by aseptic processing under
`validated and controlled conditions.
`there is a substantial likelihood that at
`least some drug products will be
`microbiologjcally contaminated. in
`addition. the sterilization method most
`frequently used for the drug dosage form
`in aseptic processing is filtration.
`Because this physical process removes.
`but does not inactivate. microorganisms.
`it cannot prevent contamination of the
`final drug product by viruses or other
`viable biological components that
`cannot be contained by a filtration
`system.
`Based on the above. the agency
`concludes that terminal sterilization.
`when properly performed. results in
`drug products with a higher statistical
`probability of sterility than those drug
`products that are aseptically processed.
`This conclusion is consistent with
`explicit statements that terminal
`sterilization is preferable and that
`sterilization by filtration is the least
`desirable method of sterilization that
`appear in the regulations of Canada. the
`United Kingdom. Australia. the
`European Pharmaceutical inspection
`Convention. and in the good
`manufacturing practice guideline of the
`European Economic Community. in
`addition. an FDA analysis of recall data
`from October 1981 to September 1991
`demonstrates that virtually all "sterile"
`drug products for human use that were
`
`MYLAN ET AL. - EXHIBIT 1023
`
`MYLAN ET AL. - EXHIBIT 1023
`
`

`
`51355
`Federal Register I Vol. 56. No. 198 I Friday. October 11. 1991 I Proposed Rules
`
`subject to the -to recalls for problems
`involving sterility had been aseptically
`processed. Some of the serious problems
`that resulted from the marketing of some
`of these products prior to their recall
`included a contaminated bone marrow
`transplant resulting from a bacterial
`contaminant in a heparin sodium
`injection used in the transplant. serious
`eye injuries resulting from contaminated
`ophthalmic solutions. and a finding of
`mold in some injections.
`All the "sterile" animal drug products
`which have been subject to the seven
`recalls between 1986 and 1991 due to
`sterility problems involved products
`which had been ascepticslly processed
`rather than terminally sterilized. While
`those recalled products which were
`implicated in adverse reactions in
`animals contained endotoxins. viable
`microorganisms [Staphylococcus
`hominis. Pseudomonos floor-escens. and
`S. co.~'tnir'] have been isolated in two
`products which were recently recalled.
`The absence of reported adverse
`reactions in animals as a result of viable
`microbial contamination of injectahle
`products may be due to a number of
`factors—adverse actions may more
`easily go undetected in animals. and
`they may go uninvestigated as a matter
`of economics andfor lower emotional
`concern.
`In 1987. FDA issued its "Guideline on
`Sterile Drug Products Produced by
`Aseptic Processing." The guideline
`recognized terminal sterilizstion's
`greater degree of sterility assurance and
`aseptic processing‘s greater risk of
`possible contamination. However. the
`guideline only provided information on
`acceptable practices and procedures for
`aseptic processing. As a matter of
`agency practice. FDA recently began
`asking applicants who are seeking
`marketing approval of sterile drug
`products for human use to use terminal
`sterilization whenever feasible.
`
`ll. Provisions of the Proposal
`
`This proposed rule codifies the
`agency's policy on the preparation of
`sterile drug products. The proposal
`would amend the regulations regarding
`CCMP [21 CFR part 211] and the
`regulations governing the approval for
`marketing of new drugs and antibiotic
`drugs for human use [21 CFR part 314)
`and new animal drugs [21 CFR part 514]
`to require manufacturers to use terminal
`sterilization when preparing sterile drug
`products. The agency proposes to state
`this policy by adding new §§2‘.l1.113[c}
`and 211.1ss[b}[1o) and by revising 21
`CFR 31Il.50[(_l][1}{ii] and
`51-t.1{b][5)[vii}[b}.
`The proposal would permit
`manufacturers to use aseptic processing
`
`methods only if terminal sterilization
`compromises product integrity. For
`example. the manufacturer could justify
`using aseptic processing by establishing
`that the drug product is heat-labile. as in
`the case of certain proteins and complex
`biological products that are not stable
`under conditions created by terminal
`sterilization methods. In some cases. the
`container closure system. for example. a
`prefilled syringe, may offer a clear
`benefit to patients but the system cannot
`withstand terminal sterilization. To
`justify aseptic processing for sterile drug
`products. and applicant should present
`scientific evidence with datashowing
`that unacceptable degradation of the
`product or container occurs as a result
`of terminal sterilization. This evidence
`may be supplied as a result of direct
`experimentation with the product in
`question. These data may include. for
`example, studies demonstrating \
`increased content of degradation
`products. loss of container integrity. or
`stability studies demonstrating other
`adverse effects after terminal
`sterilization. Such data could be
`summarized in tabular form but should
`include the methods used. Alternatively.
`and applicant may submit articles from
`the literature that provide adequate
`justification in cases where the effects
`of terminal sterilization are known. For
`example. the sensitivity of some drug
`substances to heat. and. hence.
`autoclave processing. has already been
`established and studies demonstrating
`this sensitivity have been published.
`Section 211.113 of the CGMP
`regulations requires that manufacturers
`establish and follow appropriate written
`procedures designed to prevent
`microbiological contamination of drug
`products purporting to be sterile. FDA is
`proposing to amend § 211.113 by adding
`new paragraph [cm] to require sterile
`products to be manufactured using
`terminal sterilization unless such a
`
`process will adversely affect the drug
`product. When sterile products are not
`sterilized by terminal sterilization. the
`proposal would require manufacturers
`to include in their written procedures an
`explanation of the reasons why terminal
`sterilization cannot be used. Data and
`other information demonstrating that
`terminal sterilization cannot be used
`would be retained as part of the master
`production and control records. The
`agency proposes to amend § 211.186 by
`adding new paragrs ph [b)[1t]} to state
`this requirement.
`Under the proposal atrevised
`§ 314.50(d][1)[ii) for a new drug and
`§ 514.1[b](5][vii][b] for a new animal
`drug. an applicant would be required to
`include in its marketing application a
`written justification with supporting
`
`documentation demonstrating why
`terminal sterilization cannot be used.
`Under the proposal. applicants of both
`abbreviated new drug applications and
`abbreviated new animal drug
`applications would also be required to
`comply with these requirements.
`For biological products. it is generally
`understood that most products cannot
`be terminally sterilized because they are
`not stable under the stress caused by
`the available methods of terminal
`sterilization. and potency of the product
`can be maintained only if sterility is
`assured through aseptic processing
`techniques. Therefore. the agency
`concludes that this proposed rule would
`impose a burden without any benefit
`with respect to biological products by
`requiring applicants to justify why
`terminal sterilization cannot be used
`when it has already been determined
`that such a process is appropriate for
`few. if any. biological products.
`Accordingly. this proposed rule would
`not apply to biological products. The
`agency proposes to amend § 211.113 of
`the CCMP regulations by adding new
`paragraph {cm} to state this exemption.
`Failure to comply with these
`requirements would result in a finding
`that the drug product is adultera ted
`under section 501[a][2}{B] of the Federal
`Food. Drug. and Cosmetic Act [21 U.S.C.
`351[a]{2j{B}]. It would also result in the
`agency's refusal to approval a marketing
`application for the product.
`Ill. Proposed Effective Date
`
`The agency proposes that any final
`rule based on this proposal be effective
`13 months after its date of publication in
`the Federal Register. This effective date
`reflects the time that FDA believes
`applicants may need to adapt to the new
`requirements. FDA specifically seeks
`comment on whether this is an
`
`appropriate effective date. During the
`18-month transition period, any
`applicant who cannot use terminal
`sterilization for preparing the sterile
`drug product for which it is seeking
`approval should include in its new drug.
`new animal drug. abbreviated new drug.
`or abbreviated new animal drug
`application. or in an amendment to a
`pending new drug. new animal drug.
`abbreviated new drug. or abbreviated
`new animal drug application.
`justification with supporting data
`demonstrating why terminal sterilization
`cannot be used. Any person holding an
`approved application or abbreviated
`application for a sterile new drug or new
`animal drug product that was not
`prepared by terminal sterilization
`should provide FDA with a justification
`and supporting data demonstrating why
`
`

`
`"4.
`51356
`Federal Register I Vol. 58, No. 193 I Friday, October 1‘l,'1'99i I Proposed Rules
`
`term inal sterilization cannot be used. or,
`if the product can be terminally
`sterilized. a supplemental application
`under § 314.70[b][2] or § 51-t.8[a][4] [21
`CFR 314.7o[b]{2]) or 514.B[a)[4})
`providing for conversion to terminal
`sterilization. The agency does not
`anticipate appreciable delay in
`reviewing a supplemental application to
`provide for terminal sterilization. FDA
`will make every effort to complete
`review of these applications as quickly
`as possible. The agency notes that
`§ 314.70{b] permits applicants to request
`expedited review of a supplement for a
`new drug for a change that requires
`prior approval.
`_
`Before the effective date of the final
`rule. any new drug. new animal drug.
`abbreviated new drug. and abbreviated
`new animal drug application under
`review by FDA on or after the date of
`publication of the final rule that does
`not provide for the use of terminal
`sterilization for preparing a sterile drug
`product that can be terminally sterilized
`may be approved it the application is
`otherwise approvable and the applicant
`agrees to convert to terminal
`sterilization by the effective date. On
`and after the effective date of a rule.
`FDA will refuse to approve a new drug.
`new animal
`abbreviated new drug.
`and abbreviated new animal drug
`application if the applicant seeks
`approval for a sterile product where
`terminal sterilization is not used and the
`applicant has not amended its
`application to include a justification
`with supporting documentation
`demonstrating why terminal sterilization
`cannot be used.
`
`IV. Environmental Impact
`
`The agency has determined under 21
`CFR 25.2:-l{a][8} that this action is of a
`type that does not individually or
`cumulatively have a significant effect on
`the human environment. Therefore,
`neitheran environmental assessment
`nor an environmental impact statement
`is required.
`'
`
`V. Economic Impact
`
`The agency has examined the
`economic impact of this proposed rule in
`accordance with Executive Order 12291.
`and has determined that the proposed
`regulation does not constitute a major
`rule. Furthermore. based on preliminary
`data. the agency certifies that this
`proposed rule will not have a significant
`economic impact on a substantial
`number of small entities. and. therefore:
`does not require a regulatory flexibility
`analysis under the Regulatory Flexibility
`Act of 1980 (Pub. L. 95-354}.
`This proposed rule would require.
`where appropriate. the use of a tenninal
`
`sterilization process in the preparation
`of a sterile drug product in order to
`decrease the risk of contamination that
`may be associated with other methods
`of sterilization. FDA estimates that the
`total cost to firms of converting to
`terminal sterilization would be $43
`million. This figure of$43 million is a
`combined cost for human drug
`establishments and animal drug
`establishments. The cost incurred by a
`particular establishment will depend on
`whether the firm needs to acquire new
`equipment andlor make significant
`renovations.
`The proposed regulation will require
`firms producing sterile products to incur
`two types of costs: Capital costs for new
`or additional equipment plus any
`renovation needed for installing the
`equipment; and costs for validation
`testing of the new sterilization process.
`which is needed for supplementing the
`drug applications. After consulting with
`several pharmaceutical companies who
`recently converted their facilities to
`handle the terminal sterilization of drug
`products. FDA estimates that companies
`would spend an average of $500000 to
`install an autoclave. if structural
`changes to a plant for housing the new
`equipment were necessary. FDA
`estimates that an additional szsomo
`would be incurred.
`
`The companies will also need to
`supplement the drug application where _
`there has been a change in the
`sterilization process. The average
`validation testing cost is estimated at
`about $75,000. Because more than one
`product can be validated in the same
`cycle, the costs for validation testing for
`one product is assumed to be the same
`as the costs for validation testing of
`numerous products.
`There are approximately 221 human -
`drug manufacturing establishments
`[affiliated with 153 firms} which
`manufacture sterile products [small and
`large volume parenterals and
`ophthalmic products]. The agency
`estimates that approximately 40 percent
`manufacture aseptically filled drug
`products that could be produced via a
`terminal sterilization process. Thus.
`FDA estimates that approximately 83
`human drug manufacturing
`establishments would be affected by the
`proposed rule. Based on FDA‘s
`inspection experience. a little over one-
`half [43] of the affected establishments
`are already extensively equipped with
`terminal sterilization machinery and
`trained personnel. Therefore. these 48
`establishments will incur costs only to
`run validation tests for those affected
`sterile drug products not already
`terminally sterilized. The remaining 40
`establishments. have either limited or no
`
`terminal sterilization capacity. These
`establishments will need to purchase
`‘capital equipment and run validation
`tests. An estimated 22 of these 40
`establishments may also need to make
`renovations to their plants.
`The first set of 46 human drug
`manufacturing establishments. which
`must only supplement drug applications
`with validation tests, will incur one-time
`costs of $3,000,000 [48 establishments )(
`$75,000 for validation tests] under the
`proposed rule. The second group of
`human drug manufacturing
`establishments. comprised of the
`roughly 18 establishments that will need
`an increased capacity for terminally
`sterilizing drug products, but not major
`structural changes to the plant. will
`incur one-time costs under the proposed
`rule of about $10,350,000 [18
`establishments X {$500,000 for
`autoclave + $175,000 for validation
`tcsts}]. The final 22 establishments are
`assumed to need structural changes to
`their facilities in addition to new
`autoclaves and validation tests. Thus.
`these human drug manufacturers will
`incur one-time estimated costs of
`$18.150.000 [22 establishments )<
`[$500,000 for autoclave + $250,000 for
`renovation + $75.000.for validation
`tests]].
`In total, the estimated one~time cost
`imposed on the 83 human drug
`establishments is $32 million. On an
`annual basis. assuming a 20-year
`equipment lifetime and a 10 percent
`interest rate, this amounts to about $3.3
`million per year.
`Similar average costs can be expected
`to occur in the animal drug industry.
`Officials of FDA's Center for Veterinary I
`Medicine estimate that there are roughly
`40 establishments manufacturing sterile
`animal drug products. However, 25 of
`these establishments also manufacture
`human drug products and costs
`associated with terminal sterilization for
`these establishments have been
`included under the human drug
`establishment estimate presented above
`The remaining 15 sterile animal drug
`manufacturing establishments are
`expected to experience varying CD51
`impacts. The agency estimates that 10 of
`the 15 establishments will incur initial
`costs for purchasing an autoclave,
`renovating or reconstructing. and
`performing validation testing. The cost
`to these 10 establishments totals
`$8.250.0t)0 [10 establishments )(
`{$500,000 for autoclave + $250,000 for
`renovation + $‘75.000 for validation
`tests]}. The remaining 5 establishments
`will incur costs of $2,875,000 for
`purchasing a new or additional
`autoclave and running validation tests
`
`

`
`51357
`Federal Register I Vol. 56. No. 198 I Friday. October 11. 1991 I Proposed Rules
`
`
`[5 establishments X [$500.0t}D for
`autoclave + $75300 for validation
`tests]}. Thus. the total one-time impact
`to these 15 animal drug establishments
`is estimated to be $11.125.ot}0. On an
`annual basis these costs total $1.3
`million per year.
`Total annual costs amounting to $5
`million [$3.8 million for human drugs
`and $1.3 million for animal drugs} would
`not have a substantial impact on the
`manufacture of sterile drug products as
`a whole. Nonetheless. while most larger
`firms already have terminal sterilization
`equipment in place and would
`experience few significant cost impacts.
`some smaller firms may not have
`immediate access to the necessary
`equipment and would either need to
`borrow the capital funds or revise their
`product lines. Although smaller
`operations require smaller and less
`expensive autoclaves. FDA is not
`certain that it has identified all of the
`costs that may be incurred by each type
`of establishment. Thus. the agency
`welcomes comments on the accuracy of
`its estimated costs of compliance and on
`the distribution of these impacts among
`firms of different sizes.
`In the international arena. most
`developed countries (Canada. Australia.
`and the European Economic Community
`
`Countries) already have guidelines or
`regulations or guidelines in place which
`specify terminal sterilization as the
`preferable method of sterilization. Since
`the majority of imported sterile finished
`dosage form products come from those
`countries which already prefer or
`require terminal sterilization. no adverse
`effect on imports is anticipated. In
`addition. U.S. manufacturers which
`terminally sterilize products for export
`will experience increased demand and
`reduced import restrictions. since these
`products will meet the regulations of
`other countries.
`A more detailed copy of the agency's
`assessment of the economic impact is on
`tile with the Dockets Management
`Branch [address above). All public
`comments regarding the cost of
`'
`switching from aseptic processing of a
`sterile drug to terminal sterilization will
`be reviewed and incorporated into the
`agency's final economic assessment.
`
`VI. Paperwork Reduction Act of 1980
`
`This proposed rule contains
`information collections which are
`subject to review by the Office of
`Management and Budget [OMB] under
`the Paperwork Reduction Act of 1930.
`The title. description. and respondent
`description of the information collection
`
`are shown below with an estimate of the
`annual reporting and recordkeeping
`burden. Included in the estimate is the
`time for reviewing instructions.
`searching existing data sources.
`gathering and maintaining the data
`needed. and completing and reviewing
`the collection of information.
`
`Title: Use of Aseptic Processing and
`Terminal Sterilization In the Preparation
`of Sterile Pharmaceuticals for Human
`and Veterinary Use.
`Description: This proposed rule would
`require manufacturers applying for
`marketing approval of a drugproduct to
`describe the procedures that would be
`taken to assure the drug product's
`sterility. If the manufacturer seeks
`approval for or has obtained approve] of
`a sterile drug product that was not
`prepared using terminal sterilization. the
`proposed rule would require the
`manufacturer to justify in the marketing
`application why terminal sterilization
`was not appropriate. In addition. the
`proposed rule would require a
`manufacturer who does not use terminal
`sterilization to prepare a sterile
`product to keep in its files a justification
`with supporting data demonstrating why
`terminal sterilization is not appropriate.
`Descn'ptr'on ofRespondents.‘ Business.
`
`ESTIMATED ANNUAL Fteeonnuc Ann FIECORDKEEPING Buaoen
`
`
`Annual
`A
`
`number ol
`‘rmngal
`hmhaafillpir
`'M"“ffiub"'d°"
`
`
`
`
`ell" my responserespondents '5
`
`
`
`21 1 .18-5l,'b}{10l.............
`3il.5D(Q['l )lli]I_._-_......_...........................
`514.1[bl(5l{\riJ{bl .—.-—....————-....--—-——--—--------
`
`220
`
`These estimates are an approximation
`of the average time expected to be
`necessary for a collection of
`information. They are based on such
`information as is available to FDA. The
`agency seeks comment on these
`estimates. particularly the industries‘
`view of the number of firms and
`products affected by the collections of
`information contained in this proposed
`rule.
`
`The agency has submitted a copy of
`this proposed rule to OMB for its review
`of these information collections.
`interested persons are requested to send
`comments regarding this burden
`estimate or any other aspect of this
`collection of information. including
`suggestions for reducing this burden. to
`1'-‘DA's Dockets Management Branch
`[address above]. and to the Office of
`information and Regulatory Affairs.
`
`OMB. rm. 3203. New Executive Office
`Bldg.. Washington. DC 20503. Attn: Desk
`Officer for FDA.
`
`List of Subjects
`21 CFR Part 211
`
`VIII. Request for Comments
`
`Interested persons may. on or before
`December 10, 1991. submit to the
`Dockets Management Branch {address
`above}. written comments regarding this
`proposal. Two copies of any comments
`are to be submitted. except that
`individuals may submit one copy.
`Comments are to be identified with the
`docket number found in brackets in the
`
`heading of this docurnenL Received
`comments may be seen in the office
`above between 9 a.m. and 4 p.m..
`Monday through Friday.
`
`Drugs. Labeling, Laboratories.
`Packaging and containers. Prescription
`drugs. Reporting and recordkeeping
`requirements. Warehouses.
`21' CFR Part 314
`
`Administrative practice and
`procedure. Confidential business
`information. Drugs. Reporting and
`recordkeeping requirements.
`21 CHI Part. 514
`
`Administrative practice and
`procedure. Animal drugs. Confidential
`business information. Reporting and
`recordkeeping requirements.
`Therefore. under the Federal Food.
`Drug. and Cosmetic Act and under
`authority delegated to the Commissioner
`
`

`
`51358
`Federal Register I Vol. 56. No. 198 I Friday. October 11. 1991 I Proposed Rules
`
`of Food and Drugs. it is proposed that 21
`CFR parts 211. 314. and 514 be amended
`as follows:
`~
`
`PART 211---CURRENT GOOD
`MANUFACTURING PRACTICE FOR
`FINISHED PHARMACEUTICALS
`
`1. The authority citation for 21 (_IFR
`part 1211 continues to read as follows:
`Authority: Secs. 201. 501. 502. 505. 505. 50?’.
`512. F01. .704 of the Federal Food. Drug. and
`Cosmetic Act [21 U.S.C. 321. 351. 352. 355. 358.
`357. 36Gb. 371. an].
`
`2. Section 211.113 is amended by _
`adding new paragraph [c] to read as
`follows:
`
`§ 211.113 Control of microbiological
`contamination.
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`[c}[1] Drug products purporting to be
`sterile shall be sterilized by terminal
`sterilization unless such process will
`adversely affect those drug products. In
`cases where terminal sterilization is
`determined by the manufacturer to be
`inappropriate. the written procedures
`described in paragraph [b] of this
`section shall include a justification for
`this determination.
`[2] Biological products for human use
`are exempt from the requirements of
`paragraph {c]{1] of this section.
`3. Section 211.188 is amended by
`adding new paragraph (b][1t]} to read as
`follows:
`
`§2t1.1B6 Master production and control
`records.
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`(101 in cases where terminal
`sterilization is determined by the
`manufacturer to be inappropriate.
`documentation supporting the
`justification included under
`§ 211.113{c]{1].
`
`PART 3‘|4—APPLlCATIONS FOR FDA
`APPROVAL TO MARKET A NEW DRUG
`OR AN ANTIBIOTIC DRUG
`
`at. The authority citation for 21 CFR
`part 314 continues to read as follows:
`Authority: Secs. 201, 301. 501. 502. 503. 505.
`506. 509. 701. 703 of the Federal Food. Drug.
`and Cosmetic Act [21 U.S.C. 321. 331. 351. 352.
`353. 355. 356. 35?. 371. 3?6].
`
`5. Section 314.50 is amended by
`revising paragraph [d]{1}[ii] to read as
`follows:
`
`§ 314.50 Content
`application.
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`tormat at an
`t
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`Id! ' : :
`_
`I
`[1] '
`[ii] Dr-ugpnoduct. A list of all
`components used in the manufacture of
`
`the drug product (regardless of whether
`they appear in the drug product]; and a
`statement of the composition of the drug
`product; a statement of the
`specifications and analytical methods
`for each component: the name and
`address of each manufacturer of the
`drug product: a description of the
`manufacturing and packaging
`procedures and in-process controls for
`the drug product: such specifications
`and analytical methods as are necessary
`to ensure the identity. strength. quality,
`purity. and bioavailability of the drug
`product. including. for example.
`specifications relating to sterility.
`dissolution rate. containers and closure
`systems: and stability data with
`proposed expiration dating. The
`application may provide additionally for
`the use of alternatives to meet any of
`these requirements. including
`alternative components. manufacturing
`and packaging procedures. in-process
`controls, methods. and specifications.
`Reference to the current edition of the
`U.S. Pharmacopeia and the National
`Formulary may satisfy relevant
`requirements in this paragraph. The
`application for a sterile drug product
`that is not sterilized by terminal
`sterilization shall include a written
`justification with supporting
`documentation demonstrating why
`terminal sterilization is not appropriate.
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`PART 5‘l4—NEW ANIMAL DRUG
`APPLICATIONS
`
`ti. The authority citation for 21 CFR
`part 514 continues to read as follows:
`Authority: Secs. 501. 502. 512. ‘I01. 703. 801
`of the Federal Food. Drug. and Cosmetic Act
`(21 U.S.C. 9.51.352. scab. 371. 376. set].
`
`7:’. Section 514.1 is amended by
`revising paragraph [b][5]{vii][b} to read
`as follows:
`
`§ 514.1 Applications.
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`[5] r
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`[b] If t.he article is one that is
`represented to be sterile. the same
`information with regard to the
`manufacturing. processing. packaging.
`and the collection of samples of the drug
`should be given for sterility controls.
`Include the standards used for
`acceptance of each lot of the finished
`drug. If the article is not sterilized by
`terminal sterilization. a written
`justification with supporting
`documentation demonstrating why
`terminal sterilization is not appropriate
`shall be provided.
`I-
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`Dated: May 15.1991.
`David A. ‘Kesslcr.
`Comnn'ssi'oner ofFood and Drugs.
`|F'R Doc. 91-24569 Filed 10-10-91: 8:45 am]
`BILLING coca use-or-II
`u—m
`
`
`FEDERAL EMERGENCY
`MANAGEMENT AGENCY
`
`44 CFR Parts 65 and 72
`
`RIN 30B?—AB 66
`
`National Flood Insurance Program;
`Identification and Mapping of special
`Flood Hazard Areas and Procedures
`and Fees for Processing Map changes
`AGENCY: Federal Insurance
`Administration [FIA]. Federal
`Emergency Management Agency
`[FEMA].
`ACTION: Proposed rule.
`
`SUMMARY: T