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Critical Choices

Michael Tschöpe at Excella GmbH looks at the implementation problems when developing and manufacturing drug products containing high potency pharmaceutical ingredients

The market for high potency active pharmaceutical ingredients (APIs) and drugs is steadily growing. The increasing demand is still mainly driven by the desire to develop drugs for oncological indications, but the trend towards the development of more receptor-specific, and thus increasingly potent compounds, leads to new drugs for the treatment of cardiovascular, central nervous system and other disorders. As a result the portfolio that needs to be manufactured, with consideration to special safety precautions, has left behind cytotoxics and hormonelike APIs that have long dominated high containment operations (HCO). With respect to the development and manufacturing of both highly potent APIs and dosage forms, the challenge is to merge cGMP requirements with the necessary proper protection of personnel and the environment.

HANDLING HIGHLY ACTIVE INGREDIENTS

In its simplest terms, HCO has one primary objective: to prevent the release of active compounds that may present a hazard to human and animal populations into the immediate manufacturing area and the environment in general, and to make sure that no cross-contamination occurs with other drugs manufactured on site. When it comes to manufacturing of solid dosage forms, specific care needs to be taken because many of the manufacturing technologies require high energy input and may lead to the release of particles into the immediate manufacturing environment. One approach is to build the entire process under containment, creating a sealed envelope around the critical areas where the active drug is handled and ensuring that manufacturing operations are conducted in the safest possible manner. Simply protecting the personnel with equipment such as dust masks or full air fed suits alone is not adequate.

To set up a site for a state-of-the-art development and manufacturing environment for the handling of highly active ingredients involves a large initial investment, as well as the awareness that ongoing operational costs will probably be higher compared to a conventional manufacturing environment. Besides the investment, extensive experience in the specific handling precautions that need to be taken into consideration is an additional necessity for the set-up of suitable development and manufacturing sites. In addition to costly infrastructure, many companies are faced with the challenge that the highly potent products they develop in Phase II or Phase III still experience a high failure rate, making in-house investment in HCO production difficult to justify. Far too many major pharmaceutical manufacturers have facilities originally built around one particular product that now sit idle.

DUAL CAPABILITIES

All this leads to increasing demand for contract manufacturing companies that are able to develop and manufacture highly potent active ingredients, as well as dose forms, according to the latest requirements. Ideally, both capabilities can be offered by the same contractor, in order to avoid unnecessary shipments of critical actives as well as to collaborate efficiently. While the cGMP requirements are well defined and appropriate standards are set, the selection criteria for a suitable contract manufacturer that can safely handle highly potent ingredients might be less evident. To have an OSHAS 18001 certificate alone is not nearly sufficient. In addition to a proven yearlong positive audit history of the high containment areas that can be looked up at least for FDA inspected facilities, a safety certification by well-recognised third party providers is a good indication of a proper contract manufacturing organisation.

PERSONNEL

Alongside the elements outlined in Evaluating Contract Manufacturers (page 90), the effective training of operators and other personnel in the specific requirements of running and maintaining the high containment facility is imperative. Specialised training programmes may be needed for different job functions. There are critical demands placed on operators working in high containment facilities to the extent that not following instructions can cause severe damage to both the personnel and the environment. Personnel must be trained to achieve a balance in operator comfort and production work efficiency while keeping operator safety as the highest priority. Highly detailed SOPs on training are an essential aspect of success in this area.

CONCLUSION

The high costs of building and maintaining high containment infrastructures, managing the testing, conducting worker training, and managing local and global market regulatory requirements will result in more pharmaceutical companies outsourcing development or manufacturing of high potent APIs and dosage forms. It is important to notice that a careful evaluation of the contractor’s capabilities is paramount to avoid costly delays. Facilities with a proven history of development and manufacturing under high containment, which have also passed FDA, EU and ANVISA inspections, might be the best locations to look for.

Evaluating contract manufacturers

Key indicators to look for in order to evaluate a contract manufacturer:

  • Isolator technology for bulk manufacturing and packaging available
  • Use of adequate personal protective equipment based on risk assessments in addition to engineering means
  • Remote control systems to allow operators to act from outside of the critical area
  • Automated self-adjusting machines so that operator interference, and thus potential exposure to the active drug, is minimised
  • Process analytical technology (PAT) to reduce the level of manual or automated sampling for in process control and to continually monitor critical steps of the manufacturing processes to make it more stable and reliable
  • Specially designed clean-in-place (CIP) or wash-in-place (WIP) equipment such as pre-cleanable tablet presses, capsule fillers and coaters, which reduces the need for manual cleaning activities
  • Separate production areas that utilise a negative pressure cascade to keep any contaminants captured inside the critical area. This also includes individual material and personnel locks to maintain the negative pressure in the critical area
  • Separate air-handling systems with high-efficiency particulate air (HEPA) filters in inlets and outlets, with police filters in outlets to prevent contamination of the HVAC system and the ductwork itself, and to act as a safeguard against environmental release of the active drug
  • Single pass air – no recirculation into other manufacturing areas
  • Suitably engineered docking steps in the production process, for careful transfer of active ingredient blends from one closed system to the next in the production line
  • Closed manufacturing systems with a capability of handling substances with an occupational exposure level (OEL) down to 0.1μg/m3 or even below
  • The ability to integrate the high containment elements of a production line with those elements that do not require isolation
  • The construction type and materials of the walls, ceilings and floors that need to be chosen carefully to resist repeated wash-downs and aggressive cleaning
  • Campaign manufacturing mode to separate operations with different active
  • Rigorous changeover procedures, which includes cleaning of non-product contact parts as well as walls and ceilings
  • Cleaning validation programme that covers every API manufactured in the area – no bracketing approach 
  • Use of dedicated machine parts that are assessed as difficult to clean, such as gaskets and gloves
  • Set-up of labs used for analytical testing – these must be furnished with appropriate equipment, such as safety work benches for sample preparations. Ideally, these labs should be separated from the normal lab area, with limited access
  • Industrial hygiene monitoring programme (air monitoring programme) to verify that the specified limits (Occupational Exposure Limit (OEL), expressed in μg/m3) are achieved when in operation
  • Adequate waste handling system that makes sure that all waste is collected and disposed of in accordance to the local requirements

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Michael Tschöpe, PhD, studied Pharmacy at the Johann-Wolfgang- Goethe University in Frankfurt, Germany and gained his doctoral thesis in pharmaceutical technology at Ludwig- Maximilians-University in Munich, Germany. He also has certification as a Pharmacist for Pharmaceutical Technology and Pharmacovigilance. Throughout his career he has held different positions in the pharmaceutical industry, and has been involved in the development and manufacturing of different dosage forms, including herbal products, ophthalmologic products, biotechnological freeze dried products and solid dosage forms. Since 1999 he has worked for Excella GmbH, a member of the Fareva group, and formerly Heumann PCS GmbH, in Feucht, Germany, and has been General Manager since January 2008. 
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