Pisgah Labs is a custom manufacturer of high purity fine chemicals for a variety of customers. When we decided to enter the Active Pharmaceutical Ingredient (API) market, we embarked on the planning and implementation process to provide a “best in class” manufacturing facility in full compliance with current good manufacturing practices (cGMP). This case history discusses our efforts to design, commission and meet both the letter and spirit of FDA regulations.
Design of a New Facility
The cGMP regulations, as they are written, apply to the manufacture of drugs in their final dose form, but the FDA applies the regulations to the manufacture of bulk APIs. In addition, they also apply these regulations to the manufacture of drug intermediates if the manufacture of an intermediate is a “critical” step. They define a critical step as one that affects part of the drug's characterization, such as its crystalline form or impurity profile.
Much of the cGMP regulations address architectural or civil engineering issues such as requirements for adequate lighting and waste water drainage. Lights and electrical fixtures must be cleanable, or else placed in recessed enclosures. All incoming raw materials must be approved and labeled by quality control (QC), which requires sufficient warehouse space to separate pre-approved raw materials (quarantined) from approved raw materials. Additional floor space is also required to allow segregation of quarantined and approved products and intermediates.
The FDA is flexible with its requirements for the protection of product from contamination, allowing different levels of protection based on the level of product exposure and whether the exposure occurs at a pre-critical or a critical stage of manufacture. For example, if an existing chemical plant is being converted to manufacture APIs, temporary plastic curtains can be placed around reactors to provide isolation during times when the reactor is open (such as during the charging of solids through the manway or transfer of solids from the centrifuge to the dryer). However, in our case, we were building a new facility rather than attempting to convert an existing one. We chose to design the highest non-aseptic level of protection available and chose the suite design to maximize control and isolation of the product.
Only one product is typically made in a suite at one time. Equipment rooms separate the suites (see Figure 1, p. 34 in printed version). All utilities, support equipment and electrical boxes are isolated in the equipment rooms, as much as smooth operation will permit; all wall penetrations are sealed. Filters are located on both vacuum and nitrogen lines. Each suite has a separate gowning room and materials staging room. Clean-room walls (which are epoxy coated), ceiling and floor allow vigorous cleaning with direct spray from a water hose. There is no piping or equipment above the reactor manways or dryer manway to accumulate dust and potentially contaminate the product.
A dedicated HVAC system supplies air to each suite and provides a positive pressure to the suite to minimize outside contamination. The HVAC recycles air with either 95% or high efficiency particulate air (HEPA) filtration, depending on production requirements. Because recirculation of flammable vapors could potentially create a dangerous situation, lower explosive limit (LEL) sensors are located in the HVAC return air ducts. The air handler controller will automatically switch to full exhaust if flammable vapors are detected at a concentration of 25% or more of LEL.
Although the first suite is under a positive pressure to the rest of the building, the second suite can be under either a positive or a negative pressure. A negative pressure is desirable when compounds such as radioisotopes or cytotoxic drugs are being manufactured.
USP-grade water runs in a continuous loop from the holding tank, throughout the plant, and back to the holding tank. The recirculation pipe has “drops” at each point of use, but no deadlegs (dead-end pipes at least five pipe diameters long). The water entering the loop is treated with UV sterilization and 0.2µ filtration to remove bacterial contamination. This meets the requirement that water does not introduce contaminants into the product.
As construction comes to a close, commissioning begins. Commissioning is the step in which equipment is prepared for startup. Installed piping and equipment is compared to the piping and instrumentation diagram (P&ID), utility connections are confirmed, as-built drawings are prepared, equipment is started to confirm power and motor rotation, instruments are calibrated and control loops are tuned. This is a traditional engineering activity, and it is also a cGMP requirement. However, for a pharmaceutical facility, it is called equipment qualification and the documentation requirements are more extensive than they are for traditional commissioning. As with commissioning, equipment qualification is typically performed by the engineering department with assistance from manufacturing and QA departments.
Qualification is the documented action of showing that installed equipment provides consistent control of critical parameters in critical processes. It is the first step of validation, which is the process of documenting that a process or system will consistently produce the desired results. As the saying goes, “Quality can’t be tested into a product; it must be built into the product.”
Qualification documentation is formalized so that an outside auditor (who may not be an engineer or chemist) can confirm what was done. This documentation includes a page for recording data on any test instruments used in the qualification and a page to record any deviations from the established protocol. The deviations page requires the endorsement of the QA department. A typical size for a qualification document is 15 to 30 pages, not counting vendor specification sheets, O&M manuals and engineering drawings.
A list of critical equipment and systems at our facility that required qualification is given in Table 1 (left). Non-critical items are still commissioned, but do not require qualification. Non-critical systems are those that do not contact the product, including the fire protection and security systems, breathable air systems, cranes and hoists. It should be noted that the QC laboratory also has to perform similar qualification of their equipment.
Equipment qualification can be broken down into Installation Qualification (IQ) and Operational Qualification (OQ). For the most part, IQ is performed before the power is turned on, while OQ is the actual operating of the equipment. To simplify documentation, IQ and OQ may be combined into a single equipment qualification, but we chose to leave them as separate documents and will address them as such here.
After IQs and OQs are completed, a final report is written confirming that the required steps were completed. Engineering, manufacturing and QA signatures are required on this report.
A sample page from the IQ of one of our reactors is shown in Figure 2 (p 38 in printed version). The IQ includes pages that:
• Record all nameplate data: document sizes and model numbers of pumps, heat exchangers, valves, and filters.
• Verify that equipment was installed as specified.
• List all materials of construction that will be in contact with the product.
• Identify lubricants: lubricants in the reactor agitator’s shaft seal must be food grade or FDA-approved. We used a mineral oil shaft seal and applied an FDA-approved grease to dump valve threads. These restrictions did not apply to equipment that was not in product contact, such as the circulating pump for the reactors’ jacket oil or the bearings on the HVAC fan motor (however, this restriction would apply if the fan’s bearings and motor were in the air stream).
• Verify that proper utilities have been installed, including the voltage on all three legs of three-phase power brought to the equipment, as well as the instrument air, hot oil and chilled water.
• Verify that piping is leak free before it is insulated. Verify the slope of any drain piping. Note: the best time to perform this step is during the construction phase.
• Identify the critical parameters of the reactions to be carried out. Instruments used to measure those parameters will be identified as critical instruments and will require enhanced documentation. For example, the reactor temperature is critical to the product, but not the jacket temperature (although jacket temperature controls reactor temperature). Also, reactor pressure is not critical when gas phase reactants are not present, so pressure gauges are not defined as critical instruments. Pressure in a vacuum dryer may be critical, however, and must be validated and regularly calibrated. Document your rationale in the IQ for identifying instruments as non-critical.
• Document the preparation of as-built drawings (P&ID and general arrangement, for example).
• Obtain all operation and maintenance documents from equipment vendors. Prepare a list of maintenance procedures.
• Document passivation of stainless steel condensers.
• Document the known history of used equipment. This makes the next step (cleaning validation) easier since it lets the QC department know what potential residues may be present.
• Document cleaning and testing of the reactor to confirm removal of residues. Testing includes GC or HPLC analysis of final rinse samples (both water and methanol) and TOC analysis of swab samples. For us, the greatest difficulty of this step was finding swabs that did not contribute TOC to the sample.
As stated before, the IQ can be mostly performed without turning on the equipment. It is during the OQ that the engineer confirms that equipment operates as expected. Writing the protocol for the OQ requires set acceptance criteria for each test. For instance, if a certain vacuum is required in the vacuum dryer, the tester must document that the required vacuum was obtained.
For a batch facility like ours, where the same reactors, centrifuges and dryers are used to make many different products, it was important to write the protocol for the equipment OQ to cover all anticipated process or product applications. Otherwise, the OQ would have to be repeated for new products. It is also important to operate the equipment over the range that it might be reasonably expected to cover.
The OQ includes pages to:
• Calibrate critical instruments and determine the frequency of future calibrations. Critical instruments must be calibrated against another instrument that is used as the plant standard. The plant standards must periodically be sent outside for calibration against a NIST standard. Traceable standards are an important feature of any quality program and their use, availability and certificate of analysis or calibration should be included in the documentation.
• Test and document each control valve, switch, recorder and every other hardware control element.
• Test and document that reactors, centrifuges and dryers can be inerted and vented and can be pressurized with nitrogen.
• Test pressure vessels under vacuum and pressure.
• Test and document manual and automatic operation of the equipment. In the case of the reactors and dryers, we filled them with water and tested the ability to heat and cool and to hold a set point. This step should be done at the minimum and maximum liquid level expected in the equipment and over the range of temperatures expected.
• Record the amperage draws of equipment during the operation and compare them to the nameplate data.
• Configure controllers and tune control loops. Document all settings.
• Test operation of the HVAC. Positive suite pressure was documented in both recirculation and exhaust mode. We documented proper operation of the temperature control and the alarms (LEL, freeze protection, fire protection).
• List Standard Operating Procedures (SOPs) associated with new equipment. Since some critical parameters are controlled (or at least affected) manually, SOPs and operator training are like critical instruments. Engineering worked with manufacturing to prepare SOPs and provide documented and verified training.
• Write Maintenance Procedures and deliver to the maintenance department. Make these realistic and specific. O&M manuals frequently had generic lists of maintenance procedures with many procedures that did not apply to the models we purchased.
Qualification of the nitrogen system required enhanced documentation, since nitrogen contacts the product. Raw material testing is required on each delivery before it is pumped into the liquid nitrogen tank, so a testing procedure was written. This added precaution comes at a premium, since it requires that our nitrogen supplier coordinate delivery with the QC Unit.
After QA signed the qualification documents, they became controlled documents. This means that a change control form must be prepared and approved through QA to make any changes to the equipment. Such changes might include adding additional drops to the USP water loop, extending the utilities to a new reactor or reprogramming the controllers.
Change control can be constricting. It requires the engineer to obtain prior permission before altering or optimizing plant equipment. This tends to lock in practices and creates a barrier to change. However, it is designed to prevent one individual or department from making changes without notifying other departments. As a communication tool, the change control procedure prevents optimizing a single function at the expense of the overall facility.
Most of the equipment is declared ready for use after the OQ. However, the USP water system required a Performance Qualification (PQ) after the OQ was completed. The PQ applies more to a process or a system than to a piece of equipment; it confirms that the system produces a consistent product, day after day.
A PQ of the other utilities was not performed because, with the exception of nitrogen, they do not contact the product. Qualification of nitrogen was handled as described above. Although the hot oil and chilled water systems are used to control reactor temperature, which is a critical parameter, neither of these systems requires validation beyond routine equipment qualification.
Whereas engineering had performed most of the IQs and OQs, QA took over for the USP water PQ. The USP water system had to be proven to meet USP standards consistently, including standards for conductivity, TOC and microbial load. This required daily samples from each sample point for one month, which was long enough to encompass several idle periods (such as weekends) and loop sanitizations. In addition to collecting samples for analysis by a local water quality lab, resistivity is measured on-line and recorded weekly and whenever a sample is collected.
Microbial load is controlled by periodic sanitization of the entire USP water system. We adapted a procedure from one of our clients, a large pharmaceutical manufacturer, in which enough bleach is added to the system to bring the chlorine residual to 60-75 mg/L. This chlorinated water is circulated throughout the system for at least two hours and then discharged. The system is then flushed and refilled.
Problems were initially encountered with TOC measurements. This turned out to be the result of using alcohol to sanitize the sample points. After the disinfectant was switched to bleach, followed by more thorough flushing, the USP water system was able to meet TOC limits.
Guidelines for Streamlining Qualification
In our case, the same people who prepared the qualification protocols completed the qualification packages and wrote the final reports. This gave us a perspective on the process from start to finish that has allowed us to perform the qualification process efficiently. We offer the following tips.
• Write the Qualification protocols using standard templates. These templates should be prepared by the engineering department, since they are most familiar with the equipment. Make the protocol specific to the equipment. A template that is too generic will increase time and paperwork needlessly.
• Make sure that acceptance criteria are reasonable. The acceptance criteria should be set somewhere between what the vendor claims and what the process requires.
• Prevent duplication. Make installation, start-up testing and any installation performed by the vendor part of the IQ and OQ, rather than repeating these tests. Making pages from the IQ and OQ documents part of the vendors’ turnover package is a simple way to accomplish this goal. In addition, the construction manager will be confirming leak testing and drainage testing on piping anyway, so have him/her complete these portions of the IQ.
• Revalidation after changes (made through proper change control procedures, of course) usually does not need to be as in-depth (and expensive) as the original qualification. For instance, after extending the USP water loop piping and adding new drops, only limited water testing was required to confirm that cleaning and sanitization were effective.
Successfully commissioning the new facility to cGMP standards has let Pisgah Labs enter the contract manufacturing market for APIs. Our facility began production of a commercial drug product soon after commissioning. Our client performed an audit before manufacturing that found no room to comment on the manufacturing facilities or the qualification of equipment. After we began manufacturing, the FDA’s Pre-Approval Inspection (PAI) did not produce any deficiencies related to facilities or equipment. For Pisgah Labs, this served as a confirmation of our ability to design, commission and operate a cGMP bulk pharmaceutical manufacturing plant. n
Guides For New Facilities, Volume 1, Bulk Pharmaceutical Chemicals, First Edition, International Society of Pharmaceutical Engineering. June 1996
Streamlining Validation, by the ISPE San Francisco/Bay Area Chapter, in Pharmaceutical Engineering. January/February 1998, pp. 8-24.
Abbreviations and Terminology:
API – Active Pharmaceutical Ingredient.
cGMP – Current Good Manufacturing Practice. These FDA regulations for pharmaceutical manufacture can be found in 21 CFR 210 and 211.
Change Control – A formal system where changes to equipment and/or documents require a review by the appropriate departments. This may include engineering or manufacturing and, at Pisgah Labs, always includes the quality control unit.
Commissioning – The steps that take place after construction, but before startup. This includes checking motor rotation, stroking automatic control valves and calibrating instruments. See also, Qualification.
Critical Parameter – A processing parameter (e.g., temperature) which directly influences the drug characterization or impurity profile of a drug in a critical step.
Critical Step– A process step that affects part of the drug’s form in a way that will not be compensated for in further steps. For example, by introducing an impurity that will not be removed by downstream purification steps.
Exposed – A point in a process where the product is exposed to the room environment. For example, during loading or unloading of a dryer.
FDA – The U.S. Food and Drug Administration.
HEPA filter– High Efficiency Particulate Air Filter. A filter with an efficiency of at least 99.97% for 0.3µ particles.
HVAC – Heating, Ventilation and Air Conditioning.
IQ – Installation Qualification. Documented verification that piping and equipment has been installed as intended. This is essentially the portion of commissioning that can be performed without operating the equipment.
LEL – Lower Explosive Limit.
OQ – Operation Qualification. Documented verification that equipment and systems perform as intended throughout the anticipated operating ranges.
P&ID – Piping and Instrumentation Diagram.
Qualification – The documentation that equipment has been installed correctly, works correctly and consistently gives the expected results. Qualification differs from Commissioning primarily in the greater level of documentation required.
USP water – Deionized water that meets standards set by the US Pharmacopeia standards for total organic carbon, conductivity and microbial load.