Reference Section

Regulator y Guidance for Manufacturing Sterile Pharmaceutical Products Recent EC and FDA Developments
a report by

Dr Hans H Schicht
Executive Secretary, Swiss Society for Contamination Control (SRRT)

New Regulatory Guidance Published in Europe and the US

products. It covers terminally sterilised products as well as products manufactured aseptically. Both regulatory guidance documents make reference to the International Organization for Standardization (ISO) series of clean room technology standards. Indeed, they rely on them for implementing the regulatory requirements regarding design, construction, qualification and monitoring of contamination control systems.
The ISO and European Committee for Standardization Series of Clean Room Standards

In recent months, new regulatory guidance for the manufacture of sterile medicinal products was published on both sides of the Atlantic: In August 2003, the US Food and Drug Administration (FDA) published a second draft of a revised guidance document on sterile drug products produced by aseptic processing.1 In September 2003, a revised edition of Annex 1 devoted to the manufacture of sterile medicinal products to the Good Manufacturing Practice (GMP) guideline of the European Community (EC) entered into force.2 The FDA draft is a revision of a preliminary concept paper published in September 20023 as a first step towards replacing the 1987 Industry Guideline on sterile drug products produced by aseptic processing.4 It describes the FDAs current thinking and contains recommendations on how current Good Manufacturing Practice (cGMP) regulatory requirements as stipulated in the Code of Federal Regulations (CFR), Sections 210 and 211 should be interpreted by industry. The revised Annex 1 replaces previous wording, which came into effect on 1 January 1997. It is an integral part of the GMP guideline of the EC for the manufacture of medicinal products and provides specific regulatory guidance for the manufacture of sterile medicinal

Dr Hans H Schicht is Executive Secretary of the Swiss Society for Contamination Control (SRRT) and represents Switzerland on the International Organization for Standardization (ISO) and the European Committee for Standardization (CEN) Technical Committees for standardisation in the field of clean room technology. He is an independent consultant specialising on clean room technology and contamination control, with more than 30 years of experience in this field.

Since 1990, the ISO and The European Committee for Standardization (CEN) have been jointly developing two families of contamination control standards:5 the European Standard (EN) ISO 14644 series on clean room technology in general; and the EN ISO 14698 series on biocontamination control. A compilation of the standards already issued and under development is presented in Table 1. The column status 12-03 in this table identifies the actual state of approval for each work item, the approval procedure being subdivided into the following three stages: an informal circulation as a Committee Draft, with the objective of inviting technical comments

1. Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, US Department of Health and Human Services, US Food and Drug Administration (FDA) (draft guidance for comment purposes only not for implementation, 22 August 2003). 2. Ad Hoc GMP Inspections Services Group: EC Guide to Good Manufacturing Practice Revision to Annex 1: Manufacture of Sterile Medicinal Products, European Commission, Brussels, 30 May 2003. 3. Sterile Drug Products Produced by Aseptic Processing, draft, US Department of Health and Human Services, US Food and Drug Administration (FDA), Rockville, Maryland, USA (preliminary concept paper not for implementation, 27 September 2002). 4. Guideline on Sterile Drug Products Produced by Aseptic Processing, US Department of Health and Human Services, US Food and Drug Administration (FDA), Rockville, Maryland, USA, June 1987, reprinted June 1991. 5. H H Schicht, The ISO Contamination Control Standards A Tool for Implementing Regulatory Requirements, European Journal of Parenteral & Pharmaceutical Sciences, 8 (2003) 2, pp. 3742.

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Table 1: The EN ISO Series of Clean Room Standards and their Status of Development
Document no. Short title Status 12-03

ISO ISO ISO ISO ISO ISO ISO ISO ISO ISO ISO

14644-1 14644-2 14644-3 14644-4 14644-5 14644-6 14644-7 14644-8 14698-1 14698-2 14698-3

Air cleanliness classification Testing cleanrooms for continued compliance with ISO 14644-1 Metrology and test methods Design, construction and start-up Operation Terms and definitions Mini-environments, glove boxes, isolators Classification of airborne molecular contamination Biocontamination control General principles and methods Biocontamination control Evaluation and interpretation of biocontamination data Biocontamination control Measuring the efficiency of cleaning and disinfection processes of inert surfaces

Std Std DIS Std DIS CD DIS CD Std Std DIS

05-99 09-00 09-02 04-01 07-01 06-01 02-01 12-02 09-03 09-03 02-99

Table 2: The Air Cleanliness Class Limits According to ISO 14644-1

ISO Classification No. Maximum concentration limits (particles/m3 of air) for particles of the considered sizes shown below

ISO ISO ISO ISO ISO ISO ISO ISO ISO

Class Class Class Class Class Class Class Class Class

1 2 3 4 5 6 7 8 9

0.1m0.2m 10 2 10024 10 1,000237 102 10,0002,370 100,00023,700 1,000,000237,000

0.3m 4 35 8 1,020 352 10,200 102,000 352,000 3,520,000 35,200,000

0.5m

1m 5m

83 3,520 832 35,200 83,200 832,000 8,320,000

29 8,320 293 2,930 29,300 293,000

from the nations actively involved in the development of the standard; a first formal circulation as Draft International Standard (DIS) for the parallel ISO and CEN enquiries, inviting technical and editorial comments and requesting a generic statement on the merits of the draft by means of a preliminary vote; and the second formal circulation as Final Draft International Standard (FDIS), for the parallel ISO and CEN voting leading if successful to approval and subsequent publication in the ISO and CEN collections of standards. As soon as a standard has been circulated as a DIS, it can be purchased through the national standardisation bodies. From this instant, it may be utilised as a base document for job specifications and contracts and it is considered as state of the art in any legal dispute. With five clean room standards formally approved and another four at DIS level, comprehensive guidance is currently available in this field for serving industry. The point of departure of this standardisation effort is the air cleanliness classification scheme according to EN ISO 14644-1.6 It is distinguished by a

mathematically coherent approach and based on the following formula: Cn = 10N (0,1/D)2,08 where Cn = maximum number concentration of particles per cubic metre (m3) with a diameter the considered particle diameter, rounded to a maximum of three digits; N = ISO classification number; D = considered particle diameter; and 0,1 = the reference diameter, a constant with the dimension m. Table 2 presents the ISO class limits in tabular form.
The New Edition of Annex 1 to the EC GMP Guideline

The precipitated formal adoption of the revised Annex 1 to the GMP guideline of the EC was an unpleasant surprise for many in the industry. After all, the draft had only been released for public consultation in November 2002. A mere five months later, the ad hoc GMP inspectors group responsible for the revision prepared the final draft for the subsequent formal adoption by the Pharmaceutical Committee of The European Agency for the Evaluation of Medicinal Products (EMEA). The

6. EN ISO 14644-1: Cleanrooms and Associated Controlled Environments Part 1: Classification of Air Cleanliness, May 1999.

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Regulator y Guidance for Manufacturing Sterile Pharmaceutical Products

Table 3: Room Grades for the Manufacture of Sterile Medicinal Products According to Annex 1 (September 2003) of the EC GMP Guideline At rest (b) In operation Room grade Maximum permitted number of particles/m3 equal to or above (a) 0.5m (d) 5m 0.5m (d) 5m A 3,500 1 (e) 3,500 1 (e) B (c) 3,500 1 (e) 350,000 2,000 C (c) 350,000 2,000 3,500,000 20,000 D (c) 3,500,000 20,000 not defined (f) not defined (f)
Notes af: please refer to Annex 1 directly.

many suggestions submitted by renowned bodies of the pharmaceutical industry were given no serious consideration;710 the text finally adopted is almost identical in its wording to the previous draft. The principal and most controversial changes in comparison with the previous edition concern the determinations for particles of 5m diameter and above as well as the corresponding ones for the recommended sample volume of air. The particle concentration limits according to the revised Annex 1 for the room Grades A to D are provided in Table 3. Those for particles of 0.5m diameter and above are unchanged in comparison to the previous edition, whereas the concentration limit for particles of 5m diameter and above has been changed, for the Grade A areas and for Grade B at rest, from zero to one particle 5m diameter per m3 of air. Mathematically, this is a step in the right direction; but proving a concentration value as low as one particle per m3 with statistical confidence by means of discrete-particle counters with their airflow rate of not more than one cubic foot per minute equal to 28.3 litres per minute is simply not feasible. For particles of 0.5m diameter and above, the limit values for room Grade A and for room Grade B at rest correspond with the ISO Class 5. As Table 2 shows, the corresponding ISO Class 5 limit value for particles 5m is 29 particles per m3, a limit capable of being verified straightforwardly with statistical assurance. It came as a disappointment to many professionals that the European regulatory authorities have refrained from adopting the internationally recognised ISO 14644-1 air cleanliness classes also for the particles of 5m and above. No science-based explanations have been given so far by the European regulators for the reasons behind this decision. The recommended sample volume of 1m3 of air for Grade A and B areas and preferably also for Grade C

areas is another new requirement raising a number of questions. Again, no science-based justification is offered for this determination. How is this requirement to be interpreted in practice? Is this the sum of the individual air samples taken in a work area or is this requirement to be met individually for each sampling location? If it applies to each sampling location, do the inspectors expect a continuous measurement, with a printout of the result only after a total air throughput of 1m3 through the discreteparticle counter, i.e. after a counting period of 36 minutes? Such an extended sampling period would neutralise the most welcome capability of the discreteparticle counter: to provide instant data regarding unacceptable deviations of the particle status from the desired range to which operators could react without delay. If the 1m3 could be interpreted as the sum of 36 samplings of one minutes duration each, this instant information would not be lost. Some inspectors seem to accept this summing up but is it safe to assume that this is a generally acceptable procedure? Another unfortunate determination is the requirement regarding the airflow pattern in the critical areas of high-risk operations, such as the filling and closing zone during aseptic filling of ampoules, phials and syringes. Annex 1 requires protection of such high-risk areas by laminar airflow systems, which should provide an homogeneous air velocity in the range of 0.360.54 metres per second (m/s) at the working position. Two objections must be raised here. The first concerns the term laminar airflow. Laminar airflow, correctly speaking, is an aerodynamic term signifying an airflow pattern devoid of any turbulence. Under clean room conditions, such a flow pattern is inherently unstable and cannot be maintained in a pharmaceutical filling and closing area. Using this term in the clean room technology context is a relic from the past it had been used clumsily and carelessly for many years for describing a low-turbulence airflow pattern where the air

7. S Fairchild, May 2003 Revision of the Annex 1 to the EU GMP Guide, GMP Review, 2 (2003) 3, pp. 57. 8. J Sharp, Letter to the Editor: Annex 1, ibid., pp. 45. 9. M Finke and H Schulz, Aktuelles zu GMP-Regularien (GMP Regulatory Documents: Current Issues), Pharm. Ind., 65 (2003) 10, pp. 1,0651,069. 10. H H Schicht, The Revised Annex 1 to the EC GMP Guideline, GMP Review, 2 (2003) 3, pp. 711.

Reference Section

Table 4: FDA Draft Guidance for Aseptic Processing (August 2003 Table of Contents) I. Introduction II. Background III. Scope IV. Buildings and facilities V. Personnel (training, qualification and monitoring) VI. Components and container/closures VII. Endotoxin control VIII. Time limitations IX. Validation of aseptic processing and sterilization X. Laboratory controls XI. Sterility testing XII. Batch record review: Process control documentation Appendix 1: Appendix 2: Appendix 3: Aseptic processing isolators Blow fill seal technology Processing prior to filling and sealing operation

2.5% 2.3% 1.0% 14.4% 5.5% 5.6% 1.3% 0.8% 21.7% 9.9% 7.8% 1.6% 8.9% 4.6% 3.0% 1.0% 0.9% 6.4%

References Relevant guidance document Glossary

moves on more or less parallel streamlines. In the standards literature and above all in the EN ISO standards on clean room technology, it has been replaced systematically with the scientifically correct terms unidirectional airflow or low-turbulence displacement airflow. Should GMP guidance not be expected to employ scientifically correct wording where this has become generally accepted? The second objection refers to the arbitrary fixing of numerical air velocity limits. Again, the GMP authorities owe a science-based justification for this requirement. No corresponding determinations are to be found in the EN ISO clean room standards and in the next-generation FDA guidance for aseptic manufacturing. These are just a few examples of weaknesses in the revised Annex 1. It is hoped that this unfortunate document will be withdrawn soon and replaced by determinations expressed in precise and scientifically sound wording, during the development of which competent suggestions by industrys professional bodies will be submitted to a fair, science-based assessment.
The New FDA Draft Guideline An Overview

In September 2002, a first draft of the long-expected, completely revised guidance document on aseptic processing was published as a preliminary concept paper not for implementation. Unfortunately, many of the determinations still reflected the earlier guideline and left a lot to be desired. Accordingly, many recommendations for improvement were submitted by industry (e.g. that by R Madsen11). In the second draft, published in August 2003, again intended for comment purposes only not for implementation many of these suggestions had been adopted into the text. With 2,059 lines on 59 pages, it can be considered an excellent and most comprehensive point of departure for the final editing process. Table 4 shows the list of contents of this draft; it also illustrates how much of the total text is devoted to each section. Each section begins with a listing of the applicable paragraphs of the cGMP regulations (CFR Sections 210 and 211) and is followed by detailed descriptions of what FDA currently expects from industry in order to comply with these rules. It focuses on the cGMP issues of finished drug products. Some basic determinations regarding the processing steps prior to the filling and sealing operations are addressed in Appendix 3. The air cleanliness classification scheme for work areas involved in aseptic processing is provided in Table 5. Particle concentration limits are established for particles 0.5m only and they are based strictly on and refer to EN ISO 14644-1. The identification of the air cleanliness classes, however, follows the

Since the publication of the FDA guideline on aseptic processing of pharmaceutical drugs in 1987,4 pharmaceutical technology and contamination control, as well as the corresponding technical standards, have made considerable progress.

11. R Madsen, PDA Comments on the FDA Preliminary Concept Paper Sterile Drug Products Produced by Aseptic Processing, PDA Letter, 38 (2002) 11, pp. 1, 1115.

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Regulator y Guidance for Manufacturing Sterile Pharmaceutical Products

Table 5: FDA Draft Guidance for Aseptic Processing (August 2003)
Buildings and facilities Air classificationsa

Clean area classification (particles 0.5m)

ISO designationb

Particles 0.5m/m3

Microbiological active air action levelsc (cfu/m3)

100 1,000 10,000 100,000

ISO ISO ISO ISO

Class Class Class Class

5 6 7 8

3,520 35,200 352,000 3,520,000

1e 7 10 100

Microbiological settle plates (90mm diameter) action levelsc,d (cfu/4 hours) 1e 3 5 50

Key: a = all classifications based on data measured in the vicinity of exposed materials/articles during periods of activity; b= ISO 14644-1 designations provide uniform particle concentration values for clean rooms in multiple industries. An ISO 5 particle concentration is equal to Class 100 and approximately equals EU Grade A; c= values that represent recommended levels of environmental quality. It may be appropriate to establish alternate microbiological levels due to the nature of the operation. d = the additional use of settling plates is optional; e = samples from Class 100 (ISO 5) environments should normally yield no microbiological contaminants.

traditional American practice, with the cubic feet as volume unit (as an example, Class 100 = 100 particles 0.5m per cubic foot at class limit = 3,520 particles 0.5m/m3 at class limit = ISO Class 5). All classification indications refer to the occupancy state in operation; no determinations whatsoever are made for the at-rest occupancy state. Two kinds of classified areas are distinguished: critical areas Class 100 (ISO 5); and supporting clean areas, classified as depending upon the contamination risk either Class 10,000 (ISO 7) or Class 100,000 (ISO 8). There is no direct equivalent to the European room Grade D. With regard to airflow patterns, unfortunately both the terms unidirectional airflow and laminar airflow are used in the text and, as such, rather indiscriminately. This practice is not quite coherent with the correct definition for both terms given in the glossary of the draft. However, it is encouraging to read the flow pattern requirements for points of critical exposure: laminar flow should be maintained at a velocity sufficient to sweep particles away from the filling/closing area and maintain unidirectional airflow during operations. This wording establishes clearly the objective that the airflow pattern is expected to achieve an excellent substitution for the earlier velocity requirement of 0.45m/s 20 % still being upheld by the European regulatory authorities. An exhaustive appendix is devoted to isolator technology. This is the first time for FDA to pronounce itself officially on this important new technology for the protection of aseptic filling operations.

In summation, the FDA Draft Guidance is an impressive document clarifying the FDA position in detail maybe in too much detail. The frequent use of the wording an accepted procedure is is prone to be interpreted in a narrow way as the specific procedure FDA wants to see. This may place equivalent procedures, which have not been specifically mentioned, at a disadvantage, with the risk of impeding progress.
International Harmonisation of GMP Guidance

Comparing the attitudes behind the new regulatory documents for sterile manufacturing, different philosophies seem to be followed on both sides of the Atlantic. The apparent openness to dialogue with industry so apparent in recent FDA policy and in the new-generation FDA guidance documents is not yet reflected by the European regulators. Even worse, the European and American GMP requirements for aseptic processing and the manufacture of sterile medicinal products seem to drift apart more and more. If both authorities have to be satisfied and this, nowadays, is the normal situation extra effort and as a consequence extra cost is incurred. Therefore, international harmonisation of GMP guidance documents would be a most desirable goal for the years to come. A suitable body for handling such a task already is in existence the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), a tripartite joint conference embracing the regulatory authorities of the EU, the US and Japan. This body has already established, with its GMP determinations for active pharmaceutical ingredients,12 a track record of handling such tasks competently.

12.ICH Harmonised Tripartite Guideline ICH Q7A: Good Manufacturing Practice for Active Pharmaceutical Ingredients, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, November 2000, adopted as Annex 18 into the GMP Guideline of the European Community.

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