"Production" includes all actions, steps and treatments used to manufacture a product of bioscience.  The overall goal of production can be summarized quite simply: make the product. However, in an industrial bioscience setting this description includes the use of several focused activities:

1. appropriately trained technicians / personnel (serving production, analytical and quality fucntions
2. dedicated hardware/equipment, often highly specialized
3. the use of highly detailed work instructions / methodologies (S.O.P./S.T.M.)

        "Production" cannot be considered in isolation: it is directly linked to both the analytical and quality functions. Many samples, measurements and operational conditions for specific equipment will require the interaction of "analytical" personnel and methods. The "quality system" will ensure key processing indicators (such as specific control points) have been reached and that standards and systems are all operating within clearly defined limits. We will examine but a few aspects of production, including:

	Example hardware / tools / equipment
	Individual responsibilities / actions
	Record keeping: Laboratory notebooks / forms
	Documentation: work instructions / flow charts: S.O.P.'s, S.T.M.’s
	Process deviations (PD’s), non-conformance reports (NCR’s)
	Sanitation and C.I.P. methods
	(Adequate) training

     Production includes the manufacture, development, or synthesis of a tangible / marketable commodity. Production uses many different technical tools and many types of hardware / technologies but there is a single final goal: to produce a marketable product.

This type of production often uses dedicated equipment and specifically trained personnel. Personnel will often follow strictly enforced procedures with numerous check-points and sign-offs. The product may come from virtually any starting material: plant tissue, microbial fermentations, synthetic sources or commercially-available intermediates.

In the case of products destined for direct human consumption, cleanliness, accountability and attention to detail are critical considerations. Each and every processing step, additive, treatment, or specific piece of equipment must be operating within strict limits. As well, all actions, steps or treatments must be supported by documentation that clearly displays complete accountability.

1. Hardware: Example tools and equipment of Bioscience Processing

There are many, many industrial tools used in bioscience. The tools any single bioscience industry may employ can be quite specific (depending on the nature of the product). Although a comprehensive examination of every tool employed by the many different producers of biochemicals is clearly impossible, let’s take a look at a few examples:

Storage tanks / reactors are simply these vessels are designed to hold various quantities of liquids. Most are sanitary, while others require complete sterility and aseptic technique. Many use mixing / agitation systems, air filtration, as well as sophisticated monitoring and control hardware. A "storage tank" is usually a vessel designed to hold a liquid material either for storage, transport or preparation for further processing. In contrast, we will consider a "reactor" to be a vessel in which an action or treatment is conducted. Tanks and reactors may be of virtually any size or shape, depending on the volume of the material to be handled and the nature of the specific processing step. This description includes bench-top hardware such as erlenmenyer flasks, beakers and test tubes all the way up to costly reactors with highly specific functions and volumes of thousands of liters. The vessels may be made of various plastics or high-performance polymers, but also maybe made of stainless steel or glass or a combination of a number of materials. Access to the tanks may simply be through the open "top" of the vessel, but more commonly hard or soft-plumbed lines will connect directly for liquid transfer. Valves to control liquid flow are available in a remarkable variety but an important consideration is the use of "sanitary" valves.

Connections: lines, tubing hoses. These tools provide the means through which product can be transferred and manipulated without being exposed to an "external" environment. Such connections may be hard-plumbed (permanently mounted in place) with consideration for adequate sanitation protocols, or soft-plumbed (movable hoses, clamps, tubing etc.) requiring specifc assembly and sanitation considerations.

Filtration is a simple yet powerful tool of production. In addition to remove cellular debris (and other relatively large contaminants) "microfiltration" (filtration to remove extremely small contaminants such as bacteria) is critical to ensuring and maintaining product sterility. Filtration includes many devices: large-scale industrial filter presses, bench-top filtration units, disposable sanitary cartridge-type filters and even simple syringe filters. Depending on the requirements of a particular process, al or any of the the many filtration tools maybe used.

Pumps are another important consideration as they are used to actively transfer product as required. A appropriate pump will have sufficient output to deliver the right volumes, but will also have to transfer the product with sufficient delicacy to avoid degradation. Regardless of size there is an important distinction: pumps may be sanitary or non-sanitary. A sanitary pump ensures the product does not contact the material being transferred, often an important consideration.

Chromatography Systems include many different methods and hardware. Examples include ion-exchange, size exclusion, affinity, H.I.C., and others. Columns are available in virtually and size or configuration, from 10 ml columns designed for method development to sophisticated pressurized high-throughput systems. Methods may be batch (a loose resin / gel applied directly to a solution) or column-based. Regardless of the hardware, the overall concept of chromatography in biotech production is remarkably simple: bind one (or more) components to the resin and remove / elute other components. This type of method can be a remarkably powerful purification tool when used correctly, but requires attention to detail and precision.

Specific Absorbants are sometimes employed to target specific contaminants. The absorbants may include membrane-absorbers (ie. an absorbant solid matrix) or free absorbant additives such activated carbons which can be later removed through filtration after settling.

Genetic / Molecular Processing may include hardware to conduct PCR (polymerase chain reaction) with dedicated automated systems, sequencing systems or other tools. These systems will require appropriate training in order for technicians to perform what can be often quite sensitive procedures.

    These are but a few short examples of processing equipment sometimes used in industrial bio-processing. The specific tools and equipment will be ultimately determined by the nature of the product.

2. Individual Responsibilities / Actions        

As a production technician there are many different areas of responsibility. Ultimately the goal of production is to deliver a product of satisfactory quality parameters within a specific time-frame; but this can require the concerted efforts of many different individuals. In bioscience processing, production can be divided into both "upstream" and "downstream" processing, often referring to steps earlier or later in a process.

An individual is typically responsible for completing a step (or group of steps) within a determined period of time. Actual processing may be as simple as activating a switch or a specific piece of equipment, or may require numerous interactive steps conducted simultaneously by several technicians. It is the responsibility of the production personnel to conduct their actions with a high degree of accuracy and complete accountability.

Accountability is absolutely critical in most bioscience industries: delicate, high-value products are subjected to numerous treatments with potential for product losses, degradation, loss of efficacy, potentially harmful contaminants and many other considerations. It is simply not enough for production technicians to manufacture the product: there must be extensive and complete accountability for every process step, treatment or additive used during manufacture. To maintain this high level of accountability production personnel are often subject to regular audits (intensive examinations of processing records, documentation and personnel), both internal (emanating from within the Quality system of the industry) and external (audits conducted by an "outside agency" such as a customer, a registration / certification entity or a regulatory government agency).

3. Record-keeping: Documentation / Forms        

One of the actions production personnel can use to maintain a high degree of accountability is to maintain a thorough set of production records which detail every processing step. These documents are generated through the Quality System and should effectively detail every treatment.

For routine (repetitious) procedures simplified forms are often used, requiring the technician to simply "fill in" the information for specific processing. Forms are always dated, signed (or initialed) by the technician and often signed-off by supervisory personnel to ensure critical steps have been properly conducted.

Even after a particular batch or "Lot" has been manufactured the production records are usually compiled and maintainined through the quality system. This type of record maintenance has obvious advantages: sources of batch-to-batch variation can be identified through tracking production histories and the records themselves are the technical resource necessary to support audits.

Alternatively, a laboratory notebook is a "log" of all activities and must be meticulously maintained. The lab-log type of record must be hardbound (no lose pages), have all pages numbered in sequence with no missing pages, entries are made only in ink (white-out may not be used) with any errors being "stroked out" with a single line and an initial / signature of the author acknowledging the error. All pages are appropriately titled, dated and signed of with blank spaces being filled with a single line (initialed) to discourage later alterations / entries. Such books are usually property of the institution / industry and may not be removed from the site.

The overall goal of record-keeping in production is simple: there must be documented records / accountability for all equipment and materials used (including standardization, maintenance and calibration records); accountability for all product handling / storage conditions, for all incoming materials and outgoing products. Management must be able to clearly demonstrate a product’s processing history, often years after the production was completed for any individual batch.

    Control of "errors" in records is also important. Typically all mistakes are crossed out with a single line, dated and initialed. In stricter environments a number denoting a specfic type of error must  be used (i.e. incorrect date, spelling error, calculation error, incorrect data entry, instrument error, omissions, technical error, etc.).  Often these errors require third-party sign-off and / or appropriate written explanation for closure. 

4. Documentation: work instructions//flow charts: SOP's, STM’s

With products often destined for human consumption and medical purposes most processing steps require a high level of precision. It is critical exacting procedures are maintained between different personnel, different work-shifts and production runs. Comprehensive instructions are provided: typically as "master documents" such as SOP’s (standard operating procedures) and STM’s (standard test methods). This type of documentation is prepared through the quality system and undergoes extensive review (on many levels) to provide highly descriptive and specific work instructions. These documents usually are configured to provide not only the actual "treatments", but also to provide a knowledge of the purpose, scope, responsibilities, technical definitions as well as the supporting (related) documentation and necessary flow of information.

    Example SOP / STM Contents:

	Document originator
	Reviewers
	Dates of incorporation into Quality System
	Responsibilities
	Technical Definitions
	Equipment
	Chemicals
	Actual Work Instructions
	Forms / Processing Records
	Related Documentation / SOP’s / STM’s

Information which describes all components of the production activity is recorded: either using task-dedicated forms or permanent laboratory note books.

(An example form might include considerable detail - refer to "Example SOP")

5 . Process deviations (PD’s), non-conformance reports (NCR’s)

Despite the best methods, equipment and attention to detail there will almost certainly be unexpected result complications during bioscience processing. There is an organized method of recording such events: as "process deviations"(PD); or as non-conforming product" (NCP), etc. The intention is to accurately document changes in the process / treatment or causes of the deviation, and to maintain an accurate record of the product / activities which are "out of specification". Sign-off on this type of document will certainly require supervisory sign-off and likely the involvement of the analytical and /or quality systems personnel.

This documentation should not be considered a shortcut around standard operating procedures and associated documentation, but should be reserved for product or steps which unexpectedly fall outside the documented specifications. These type of documents may be originated by production, analytical or quality personnel.  

6. Sanitation and C.I.P. methods      

Since the products of industrial bioscience are often destined for human consumption, stringent sanitation methods are a key responsibility for production personnel. Specific sanitation requirements will vary significantly depending on the nature of both the product and the specific step.

"Sanitation" may include several distinct stages: "Cleaning", the rinsing (to remove large debris / contaminants), washing with appropriate soaps /agents followed by further rinsing to remove residual soaps and contaminants. "Sanitation" is conducted on appropriately cleaned surfaces using one or more anti-microbial agents to remove contaminating microorganisms. There are usually related test procedures to confirm the correct applications of cleaners and sanitizers have been applied, as well as to test for persistent cleaning residues. These steps are of usually supported by detailed SOP protocols with detailed records.

"C.I.P." means "clean in place". This includes a variety of hardware which is cleaned, sanitized, or otherwise prepared through a dedicated cleaning process that is permanently associated with the hardware. For example: a 5,000 L tank may have a smaller (i.e. 500L) tank plumbed to it to allow technicians to recycle water, soaps and sanitizers at a specific temperature continuously with minimal interruption to the tank's normal function. Soaps / rinses can be applied through permanent internal "rotary sprayers" which deliver intense streams of cleaning solution inside the reactor / tank. This has obvious advantages: it is fast, predictable (once operating parameters have been established) and technicians are not directly exposed to the cleaning /sanitizing chemicals.

7. Training

It is assumed that professional technicians assigned to specific task will have a relevant educational background and should have a solid understanding of the general science supporting their activities. Beyond that there is almost always significant in-house training: this is necessary to enable the technician to perform up to expectation and meet all step requirements. Depending on the size of the institution there may be an entire staff dedicated to training and ensuring standards are continuously maintained. The training may include courses and programs delivered externally as well as task-specific instruction demanding competence be exhibited prior to sign-off through the quality system.

With better (more thorough) training, there are fewer the surprises for both production personnel and management since both groups have parallel expectations. Adequately trained staff are essential to all areas of industrial bioscience.

Please contact the instructor for SOP assignment # 2