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«PDHonline Course K112 (4 PDH) Fundamentals of Aseptic Pharmaceutical Engineering Instructor: Timothy D. Blackburn, MBA, PE PDH Online | PDH Center ...»

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PDHonline Course K112 (4 PDH)

Fundamentals of Aseptic

Pharmaceutical Engineering

Instructor: Timothy D. Blackburn, MBA, PE

PDH Online | PDH Center

5272 Meadow Estates Drive

Fairfax, VA 22030-6658

Phone & Fax: 703-988-0088



An Approved Continuing Education Provider

www.PDHcenter.com PDH Course K112 www.PDHonline.org

Fundamentals of Aseptic Pharmaceutical Engineering

By Timothy D. Blackburn, PE

 September, 2005 Course Content Introduction Aseptic Pharmaceutical Engineering is perhaps the most interesting to an engineer compared to other pharma/biotech projects. (Someone once said Engineers really aren’t boring people, they just like boring things.) There are two primary reasons it is a favorite. The first is the technical challenge. Things that can be overlooked in non-sterile manufacturing will present significant issues with Aseptic. The second is that there is clearer direction in regulatory directives as to fundamental scope requirements. Engineers like to begin with a firm scope.

There is less to debate, and clearer expectations as to the end product.

This course provides an introduction to Aseptic operations in the Biopharmaceutical industry. Due to the ever-changing regulatory environment, general practices will be discussed without specific reference to the predominant FDA and EU guidances as much as possible. The goal is to provide the student with a well-rounded introduction to Aseptic operations. However, refer particularly to FDA’s 21 CFR parts 210 and 211, as well as latest guidance documents. As a further and necessary disclaimer, you must evaluate each project on its own merits, and nothing herein should be considered “engineering consulting” for your specific project.

Content What is Aseptic, and why is it needed?

What do we mean by Aseptic? Aseptic simply means there are no microorganisms that can cause infection in the patient. Unlike products that are terminally sterilized (the preferred method by major regulatory agencies), an Aseptic operation maintains acceptable sterility at critical steps of the manufacturing process (when sterile filtration or other means are not possible) and filling operations (when terminal sterilization is not an option). When the product can be Page 1of 15 www.PDHcenter.com PDH Course K112 www.PDHonline.org terminally sterilized (autoclaving the most common method), Aseptic processing is not necessary.

Aseptic processing is common for parenterals (injectible drugs.) Whetherproduced in an Aseptic manner or terminally sterilized, parenterals must be sterile in their final form to avoid problems for the patient. Products that are not sterile may contain pyrogens (“an agent capable of inducing an increase in body temperature; usually refers to fever caused by bacterial endotoxins.”)1 An Endotoxin is “cell wall debris (lip polysaccharide) from Gram-negative bacteria.” 2 These may include bacteria such as E. coli, Salmanella, Shigella, Haemophilus, Pseudomonas, and Neisseria as well as other pathogens. Whereas drugs such as OSD’s (Oral Solid Dosage) do not require sterility since the body’s natural defense mechanisms engage after ingestion, parenterals are injected intramuscularly (I.M.) or intravenously (I.V.) and bypass the defense mechanisms. A simple example of this is normal drinking water. If you drink safe water, there is no ill effect. But if you were to inject the same water with a syringe, you could get extremely sick.

Especially careful formulation of parenterals is also important. A parenteral is formulated to have the same osmolarity of the blood (approximately 300 milliosmoles per liter or mOsmol/L). Solutions that have different osmalarity can cause damage to red blood cells or tissue irritation, and cause pain.

It is critical, therefore, to produce such products in an environment that mitigates

contamination and to a rigid spec. Sources of contamination include the following:

1. The product

2. The environment/HVAC

3. Equipment

4. Packaging components and materials

5. And mostly, people. As we will study later, extreme care is required to protect the product from the natural contamination of the worker. As well, it is important to design Aseptic areas that minimize the number and effort of workers.

The Manufacturing Process If the product can be sterilized prior to fill/finish1, the manufacturing process is not required to be in an Aseptic environment. However, care must be taken to minimize the Fill/Finish refers to filling the product in the final container, stoppering, labeling, etc.

Page 2of 15 www.PDHcenter.com PDH Course K112 www.PDHonline.org bioburden – we wouldn’t want to manufacture the product in the parking lot. It is common to produce products in class 100,000 cleanrooms that will be rendered sterile later.

A cleanroom class is measured by the quantity of viable (produced from living matter) and non-viable particles. The class may be referred to as other designations by regulatory agencies (for example, the EU classifies by letters A, B, C, and D), or ISO designations. (Be aware of the EU designations since they are different for at-rest and in-operation.) What does the class mean quantitatively? For class 100,000, for example, there must be less than 100,000 particles of 0.5 micron and larger particles in a cubic foot of air (there are 25,400 microns in an inch, and 1,000 in a millimeter). Although the particulates may be nonviable (non-living), they still can be an “extraneous contaminate”3 to the product, and can contaminate it biologically by acting as a microbial vehicle. Class 100,000 can be used for nonAseptic and less critical activities. (There is no specific general cleanroom classification requirement for all non-sterile drugs.) However, in the direct Aseptic area (exposed sterile product) the class must be 100, which we will discuss later. See Figure 1 below for comparative sizes of particulate.

Figure 1 – Comparative Particle Sizes

Typical sterilization techniques of the product prior to fill include heat, irradiation, and most commonly filtration through a 0.22-micron filter (or less) which is sufficient to remove most bacteria and molds (but may let viruses and mycoplasmas through). Such filters should be validated that they repeatedly remove viable microorganisms from the sterilized process stream.

These filters should be capable of a 10-3 SAL (we will discuss SAL later). Filters are tested to remove 107 Brevundimonas diminuta microorganisms per cm2 while producing a sterile effluent.4 Filters should be pre/post-bubble tested to confirm integrity.

Page 3of 15 www.PDHcenter.com PDH Course K112 www.PDHonline.org Once the product is sterilized, it is protected in a sterile state and packaged. Tanks holding or processing sterile products should be maintained in a pressurized state or otherwise sealed to prevent contamination from microbes; valves should be steam sterilizable in some applications. However, some products cannot be sterilized prior to filling, and certain process steps must be undertaken in closed or class 100 cleanroom environments (this means there are no more than 100 particles 0.5 micron and larger in a cubic foot of air), also called “Critical Areas.” The Fill/Finish Process Overview Here we reach the most critical steps of the process as it relates to maintaining sterility in a typical application. Design must be accomplished such that it is robust enough to minimize problems that lead to contamination. As well, operational aspects are crucial. At the point of entry into the Aseptic fill room, the product must be and remain sterile.

Means will be required to monitor environmental conditions on an on-going basis.

(Remote particle monitoring for nonviables is a preferred solution in addition to settling plates for viables.) Further, viable testing can include surfaces, such as room finishes, equipment, and especially sterile product contact items, containers, and closures. Such monitoring should cover all shifts. However, no amount of monitoring will guarantee sterility. Instead, the operation will rely on Validated procedures to keep the product from risk.5 Obviously, time limits should be established for each processing phase.

There are several finished forms of Aseptic produced products. One thing you might have noticed when getting that dreaded shot is that the containers are translucent. That isn’t a fashion statement – it is so a visual examination can confirm the liquid is colorless and sufficiently transparent.

What are the typical finshed forms? (See Figure 2). The most common are glass vials (single and multi-dose; if multi-dose, it should contain a preservative to permit multiple use), made of type I glass for SVP’s (Small Volume Parenterals). You are probably familiar with these, which are commonly used when receiving a vaccination (inserting a syringe needle in the top stopper, extracting the product.) Other forms include pre-filled syringes, ampoules (a sealed glass container with a long neck that must be broken off), and LVP’s (Large Volume Parenterals, typically holding 100 ml or more) in bags or bottles (type II glass).

–  –  –

The form of the final product can be powder or liquid. Also included are ointments and creams. Powder can be produced by a sterile crystallization process prior to filling the vials.

However, this tends to have a less accurate fill than liquids, as well as offer other material handling challenges. A final liquid form is often created by adding WFI (Water for Injection) to the compound and then filtered. Filtering reduces microbiological concentration of the product supply solution rendering it sterile as discussed previously. The vials can be filled with liquid, which becomes the finished form. Sterile nitrogen is used to reduce the concentration of oxygen during the filling operation. The important thing to remember is that during the fill process (while the product is exposed) the immediate environment must be a class 100 Cleanroom,2 a Critical Area. Once the stopper is installed, the over seal (arguably), labeling, and cartooning can be in a lower grade environment. Another promising technology is filling sterile liquid into vials with needles that are pre-sterilized/pre-sealed. The puncture is quickly sealed, maintaining Aseptic integrity. Also, disposable filling equipment is available.

To add additional stability to products when required, liquid can be freeze-dried after being placed in the vials but prior to complete stoppering. Often, biological materials require freeze-drying to better stabilize them. Certain products, such as proteins, don’t react well to heat, eliminating the possibility of terminal sterilization. Freeze drying is often used for vaccines, Definition of Cleanroom: “Room in which the concentration of airborne particles is controlled, and which is constructed and used in a manner to minimize the introduction, generation, and retention of particles inside the room, and in which other relevant parameters, e.g. temperature, humidity, and pressure, are controlled as necessary. ISO 14644-1, ISO 14644-3, ISO 14698-1, ISO 14698-2;” or, “The maximum number of particles greater than or equal to

0.5µm in diameter that may be present in a cubic foot of room air.” (ISPE’s online glossary, http://www.ispe.org/glossary/definitionbyterm.cfm?term=Autoclave) Page 5of 15 www.PDHcenter.com PDH Course K112 www.PDHonline.org pharmaceuticals, and blood products. A medical provider will reconstitute the product with a suitable solvent (usually WFI) prior to use. Freeze drying is called Lyophilization. Here is how it occurs. During the fill process, the vial is partially closed. Therefore, it must be maintained in an Aseptic Class 100 environment until lyophilized and finally sealed. This can present a challenge that must be thought through when designing an operation. Lyophilization consists of three distinct processes – freezing, sublimation, and desorption. Sublimation involves vaporizing a solid and condensing it without its having passed through a liquid state. Desorption involves “the release of adsorbed molecules, particles, or cells into the surrounding medium.”3 Careful consideration must be given to all Aseptic equipment. Filling equipment must be designed to be cleanable. CIP/SIP is sometimes used (Clean in place/Sterilize in place). Moist heat is common for sterilization. (Note: Sterilize is different from Sanitize. Sterilize means to destroy viable organisms and spores, whereas Sanitize reduces viable organisms to an acceptable level.) CIP can be problematic in the Aseptic area, so proceed with caution. Endotoxins on equipment surfaces can be inactivated by heat, and removed by cleaning procedures; however, autoclaving is preferred for product contact parts.4 The key to controlling bioburden is to adequately clean, dry, and store equipment. Therefore, it is essential that the design of such equipment facilitate this by being easy to be assembled/disassembled, cleaned, and sanitized/sterilized.

Another finish form/technology is BFS (Blow/Fill/Seal). This involves forming a parison (a tubular form) from a plastic polymer resin, inflating it, filling it, and sealing it in a single operation. However, at the present this method cannot accommodate Lyophilization.

For a comparative overview/PFD (Process Flow Diagram) for typical approaches, see Figure 3.

(ISPE’s online glossary, http://www.ispe.org/glossary/definitionbyterm) Definition of Autoclave: “An apparatus into which moist heat (steam) under pressure is introduced to sterilize or

decontaminate materials placed within (e.g. filter assemblies, glassware, etc.). Steam pressure is maintained for prespecified times and then allowed to exhaust. There are two types of autoclaves: 1. Gravity displacement autoclave:

this type of autoclave operates at 121ºC. Steam enters at the top of the loaded inner chamber, displacing the air below through a discharge outlet. 2. Vacuum autoclave: this type of autoclave can operate with a reduced sterilization cycle time. The air is pumped out of the loaded chamber before it is filled with steam” (ISPE’s online glossary, http://www.ispe.org/glossary/definitionbyterm.cfm?term=Autoclave)

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