Guidance for Industry Sterile Drug Products Produced by Aseptic Processing

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Guidance for Industry
Sterile Drug Products Produced by Aseptic
Processing Current Good Manufacturing Practice
Unit 2
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Introduction

• Good Manufacturing Practice (GMP) ensures that
  quality is built into the organization and
  processes involved in manufacture.
• GMP covers all aspects of manufacture including
  collection, transportation, processing, storage,
  quality control and delivery of the finished
  product.

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What is GMP?

• GMP is that part of Quality assurance which
  ensures that the products are consistently
  manufactured and controlled to the Quality
  standards appropriate to their intended use.

What is cGMP ?

• Usually see cGMP
• c current
• To emphasize that the expectations
• are dynamic.

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GMP Covers

• ALL aspects of production from the starting
  materials, premises and equipment to the training
  and personal hygiene of staff.
• Detailed, written procedures are essential for
  each process that could affect the quality of the
  finished product.
• There must be systems to provide documented proof
  that correct procedures are consistently followed
  at each step in the manufacturing process - every
  time a product is made.

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QA, GMP QC inter-relationship
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Good Manufacturing Practices

• A basic tenet of GMP is that quality cannot be
  tested into a batch of product but must be built
  into each batch of product during all stages of
  the manufacturing process.
• It is designed to minimize the risks involved in
  any pharmaceutical production that cannot be
  eliminated through testing the final product.

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Why GMP is important ?

• A poor quality medicine may contain toxic
  substances that have been unintentionally added.
• A medicine that contains little or none of the
  claimed ingredient will not have the intended
  therapeutic effect.

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• Sterile drug manufacturers should have a keen
  awareness of the public health implications of
  distributing a non-sterile product. Poor CGMP
  conditions at a manufacturing facility can
  ultimately pose a life-threatening health risk to
  a patient.

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GMPs of different countries

• At a high level, GMPs of various nations are
  very similar most require things like
• Equipment and facilities being properly
• designed, maintained, and cleaned
• Standard Operating Procedures (SOPs) be
• written and approved
• An independent Quality unit (like Quality
• Control and/or Quality Assurance)
• Well trained personnel and management

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GMP helps boost pharmaceutical export
opportunities!

• Most countries will only accept import and sale
  of medicines that have been manufactured to
  internationally recognized GMP.
• Governments seeking to promote their countries
  export of pharmaceuticals can do so by making GMP
  mandatory for all pharmaceutical production and
  by training their inspectors in GMP requirements.

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Validation and Qualification

• It is a requirement of GMP that manufacturers
  identify what validation is needed to prove
  control of critical aspects of production.
• Significant changes to the facilities, equipment
  and processes which may affect the quality of the
  product should be validated.

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Validation

• All action proving, in accordance with the
  principles of GMP that any procedure, process,
  equipment, material, activity or system actually
  leads to the expected result.

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Validation Framework
Validation Policy
Validation Plans
Process/ Equipment Etc. list
Validation Master Plan
Senior Management
Standard Operating Procedures
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Validation Master Plan

• Describes what to validate not how to
• validate defined in SOPs
• Defines the validation lifecycle
• Roles and responsibilities
• Documentation
• Change control
• Review Revalidation

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• 1. Whats the intended use of this guidance
  document?
• 2. What does the Submission Guidance describe?
• 3. Why the Agency is developing this guidance
  document?
• 4. What is the difference between sterile drug
  products using aseptic processing and production
  using terminal sterilization?

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1. Whats the intended use of this guidance
document?

• This guidance is intended to help manufacturers
  meet the requirements in the Agency's current
  good manufacturing practice (CGMP) regulations
  (2l CFR parts 210 and 211) when manufacturing
  sterile drug and biological products using
  aseptic processing.

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2. What does the Submission Guidance describe?

• The Submission Guidance describes the types of
  information and data that should be included in
  drug applications to demonstrate the efficacy of
  a manufacturer's sterilization process. This
  guidance compliments the Submission Guidance by
  describing procedures and practices that will
  help enable a sterile drug manufacturing facility
  to meet CGMP requirements relating, for example,
  to facility design, equipment suitability,
  process validation, and quality control.

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3. Why the Agency is developing this guidance
document?

• A. Regulatory Framework

This guidance pertains to current good
manufacturing practice (CGMP) regulations (21 CFR
parts 210 and 211) when manufacturing sterile
drug and biological products using aseptic
processing. For biological products
regulated under 21 CFR parts 600 through 680,
210.2(a) and 211.1(b) provide that where it is
impossible to comply with the applicable
regulations in both parts 600 through 680 and
parts 210 and 211, the regulation specifically
applicable to the drug product in question shall
supercede the more general regulations.
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3. Why the Agency is developing this guidance
document?

• B. Technical Framework

There are basic differences between the
production of sterile drug products using aseptic
processing and production using terminal
sterilization.
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4.1. The production using terminal sterilization

• Terminal sterilization usually involves filling
  and sealing product containers under high-quality
  environmental conditions. Products are filled and
  sealed in this type of environment to minimize
  the microbial and particulate content of the
  in-process product and to help ensure that the
  subsequent sterilization process is successful.
  In most cases, the product, container, and
  closure have low bio-burden, but they are not
  sterile. The product in its final container is
  then subjected to a sterilization process such as
  heat or irradiation.

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4.2. The production using aseptic processing

• In an aseptic process, the drug product,
  container, and closure are first subjected to
  sterilization methods separately, as appropriate,
  and then brought together. Because there is no
  process to sterilize the product in its final
  container, it is critical that containers be
  filled and sealed in an extremely high-quality
  environment.

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CGMP regulations

• 21 CFR 211.46(b) states that Equipment for
  adequate control over air pressure,
  micro-organisms, dust, humidity, and temperature
  shall be provided when appropriate for the
  manufacture, processing, packing, or holding of a
  drug product.

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• 21 CFR 211.46(c) states, in part, that Air
  filtration systems, including pre-filters and
  particulate matter air filters, shall be used
  when appropriate on air supplies to production
  areas .
• 21 CFR 211.63 states that Equipment used in the
  manufacture, processing, packing, or holding of a
  drug product shall be of appropriate design,
  adequate size, and suitably located to facilitate
  operations for its intended use and for its
  cleaning and maintenance.

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Glossary

• Airlocks should be installed between the aseptic
  manufacturing area entrance and the adjoining
  unclassified area.

Air lock A small room with interlocked doors,
constructed to maintain air pressure control
between adjoining rooms (generally with different
air cleanliness standards). The intent of an
aseptic processing airlock is to preclude ingress
of particulate matter and microorganism
contamination from a lesser controlled area.
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• A result at the alert level urges attention to
  the approaching action conditions.

• Alert Level An established microbial or airborne
  particle level giving early warning of potential
  drift from normal operating conditions and
  triggers appropriate scrutiny and follow-up to
  address the potential problem. Alert levels are
  always lower than action levels.

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• In the absence of any adverse trend, a single
  result above an action level should trigger an
  evaluation and a determination about whether
  remedial measures may be appropriate.

Action Level An established microbial or
airborne particle level that, when exceeded,
should trigger appropriate investigation and
corrective action based on the investigation.
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• Only personnel who are qualified and
  appropriately gowned should be permitted access
  to the aseptic manufacturing area.

Aseptic Manufacturing Area The classified part
of a facility that includes the aseptic
processing room and ancillary cleanrooms. For
purposes of this document, this term is
synonymous with aseptic processing facility as
used in the segregated segment context.
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• As provided for in the regulations, separate or
  defined areas of operation in an aseptic
  processing facility should be appropriately
  controlled to attain different degrees of air
  quality depending on the nature of the operation.

Aseptic Processing Facility A building, or
segregated segment of it, containing cleanrooms
in which air supply, materials, and equipment are
regulated to control microbial and particle
contamination.
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• Asepsis is fundamental to an aseptic processing
  operation.

Asepsis A state of control attained by using an
aseptic work area and performing activities in a
manner that precludes microbiological
contamination of the exposed sterile product.

• The number of personnel in an aseptic processing
  room should be minimized.

Aseptic Processing Room A room in which one or
more aseptic activities or processes is performed.
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Any Questions?