Production and process control

The ultimate goal of a manufacturer is to manufacture products that conform to the required specifications, and also with high level of quality assurance. Products of consistent quality can only be realized through consistent production procedures that have been developed, tried-out, and validated for the purpose.

Two basic components of a robust GMP are: SOPs that have been validated for their performance output; and that these procedures are adhered to during manufacturing. This concept of controlled application of procedures applies to every production and test procedure.

8.7.1. Product specifications

The manufacturer, having identified the products that will be manufactured, must begin with defining the product specifications. These are

generally derived from the national or international pharmacopoeias. While setting the product quality standards, it is also important to specify the allowed variance for each of the quality parameters. Procedures for manufacturing and testing are then developed and the product is evaluated against the established specifications. Zeroing-in on methodologies with consistent output is typically an interactive process, where several modifications and/or fine tuning are required. The validated procedure is then written as a SOP in simple and clear language, and with sufficient detail as to how things are to be done to ultimately achieve the desired product specifications.

8.7.2. Standard operating procedures

SOPs are the road maps derived from the procedures developed for product realization. For effective control of these official documents, manufacturer should establish a clear policy for initiation, review and approval of the SOPs. Furthermore, a mechanism must be developed and practiced for controlled issuance and usage of the approved SOPs.

The most important SOP in manufacturing is the production master batch record, or in short, a batch record (BR). The BR should describe in sufficient detail the tasks to be performed and the multiple steps involved in manufacturing the product to ensure that even when used by different individuals, results would be the same. An advantage of such a detailed procedure is that it allows easy investigation of a cause in case of a failure. A typical BR contains all the necessary information as to the date of manufacture, product lot number, calibration and expiration dates, identification and quantities of all the raw materials, equipment, and how things are to be done during the manufacturing process. It must be noted that only the approved raw materials must be used in manufacturing the product; the raw material lot numbers and quantity are entered in the BR at the time of manufacturing. All entries in the BR are initiated by the operator, and all critical steps and calculations are independently checked by another operator or supervisor, and concurrently initialled by both the operator and the checker. A typical batch record and SOPs are shown in Appendix IV.

Developing a production BR requires substantial effort even if

‘borrowed’ from a reliable source. During development stage, which should be in coordination with the QC/QA unit, the production process is performed repeatedly until it yields the desired results with a high degree of consistency.

Additional time spent in developing a sound process is worth the effort, as it will result in a product that repeatedly conforms to the required specifications, affording a very low failure rate. It must be emphasized that the goal of any production process should be to design quality into the product and its

production process. When coupled with the supporting validation data, the potential for consistently achieving quality standards is substantially increased.

To demonstrate clearly whether a process is in control, manufacturer should evaluate achieved product specifications in correlation with processing parameters (trending).

It must be noted that the product is qualified as being manufactured under GMP conditions only if the production processes are performed according to the approved and documented batch record (BR) and the applicable SOPs. Any deviation, inadvertent or intended, must be recorded and justified. The product batch must not be released for patient use if quality of product is in doubt or there is evidence of deviation from the established procedures.

Procedure modification is always a possibility for continuous improvements. In fact, such initiatives should be encouraged. However, caution is advised. Whenever a change is to be introduced in an existing procedure, the modified procedure must have been evaluated with respect to the impact on product quality. Furthermore, prior to implementation, the modified procedure must be validated and the staff must be informed of the change and also must be trained in use of modified procedure. Controls should be developed for avoidance of inadvertent use of the ‘retired’ procedures by removing it from circulation.

8.7.3. Finished products

The finished product is held in quarantine until the time that a representative sample has been tested for conformity to the pre-established quality specifications. For a small batch, which is usually the case in radiopharmaceuticals manufacturing, sampling is not necessarily based on a particular statistical method. Facilities engaged in production of PET radiopharmaceuticals are faced with situations arising from short half-life of the PET isotopes. Explicit arrangements are required to coordinate delivery time (to the user) and the time spent on quality assessment of the batch.

8.7.4. Product release

The finished product should be held in quarantine while it is being tested for conformity to pre-determined specifications. When all the necessary requirements of quality assurance for adherence to GMP are demonstrated, the batch is released for patient use. The manufacturer should designate clearly the finished product release authorization (either a designated person or a position).

A product failing to meet the established specifications or other quality criteria (for example, non-compliance with GMP) must be rejected.

Circumstances leading to a failed product should be carefully evaluated. The cause of failure should be investigated, and procedures should be established for systematic evaluation of a failed product (a written and approved SOP should be available). Reprocessing may be performed in some instances, but only as per previously written and approved procedures. The reprocessed product must conform to all the specifications prior to approval for release.

Frequency of reprocessing must be absolutely minimal. Excessive reprocessing represents a poorly validated process and loss of control in the system.

8.7.5. Reserve sample

A representative sample(s) of the batch must be set aside for retrospective testing in case of a customer complaint or query related to the product quality. Reserve sample consists of at least twice the quantity necessary to perform all the tests required to determine product quality. The duration of reserve sample retention varies among various GMP guidelines but most require 1 year.

8.7.6. Stability testing

Product stability data are required to determine the appropriate storage conditions and expiration time. For every product, it is necessary to perform stability studies to predict and confirm the product shelf-life under the climatic conditions expected, during product shipping and storage, and to establish storage conditions and expiration times. The test product should be held in the same container and closure system in which the product will be finally packaged.

8.7.7. Processes

The process of radiopharmaceuticals manufacturing is a combination of a number of subprocesses and procedures. The terms ‘process’ and ‘procedure’

are often used interchangeably; but in general, a process is of higher level than a procedure, and that a process may be composed of a number of procedures.

For example, the manufacturing of a ²⁰¹Tl radiopharmaceutical begins with the process of isotope production, which consists of a number of procedures, including irradiation of ²⁰³Tl target material in the cyclotron, followed by isolation of the ²⁰¹Pb radiochemical, growth of ²⁰¹Pb into ²⁰¹Tl, separation of

201Tl bulk radiochemical, in-process testing of the ²⁰¹Tl bulk, formulation,

sterilization, and the finished product testing. In fact, there are a number of additional procedures that also come into use before a radiopharmaceutical batch is approved for release. Well developed processes are such that, when applied as written they are most likely to have consistent output every time.

Control and monitoring of processes is part and parcel of the GMP, and should be the responsibility of not just the supervisors, but also that of the operators. It is essential to verify that the operators have comprehended and indeed followed the procedures during production of every batch of the product. Therefore, it is important for supervisors to continue the education and training of the operators at regular intervals, and to monitor all procedures and implementation thereof.

8.7.8. Deviations

In spite of the application of validated procedures, there are likely to be occasions when processes do fail. There may also be either an accidental, inadvertent or intentional deviation in the process. As an operations policy and philosophy, intentional deviations from the written procedures must not be allowed. If a deviation has occurred during production of a batch, for whatever the reason, it should be fully investigated. Product may or may not be released depending upon severity of deviation. Further evaluation and analysis of the deviation should ensue to uncover root cause of the problem such that a recurrence is eliminated. Clear policies should be established for investigation, recording, and disposition of the affected product batch.

8.7.9. Reprocessing

A batch of the radiochemical bulk or radiopharmaceutical that fails to conform to the pre-determined specifications should be considered rejected. In some simple circumstances (for example, pH and concentration adjustment), the batch may be reprocessed with consent of all the concerned parties such that the reprocessed batch is made to conform to the specifications. Procedures for reprocessing should be carefully evaluated, validated and written as SOPs.

Because of the radiation protection considerations, it should be ensured that reprocessing does not cause undue radiation burden to the operator.

8.7.10. Aseptic processing

Radiopharmaceuticals must conform to the acceptable level of microbial contamination. Certain radiopharmaceuticals with a very short shelf-life or being heat labile may not be subjected to steam sterilization in the final sealed

container. In such cases, assurance of microbial quality can only be achieved through application of aseptic processing and handling, and clean air environment. For aseptic processing, controlled environment of Class 100 conditions, with additional requirements for the surrounding buffer zone (normally Class 10.000) is required. Furthermore, a typical aseptic processing may entail assembly of product components sterilized in different ways: dry heat sterilization for glass vials; steam sterilization for stoppers; and sterile filtration of the liquid dosage form. Each of the individual procedure should be validated and carefully controlled. It should be understood that the risk of product contamination is proportionately higher in aseptic processing, necessitating much greater control of the process.

8.7.11. Radiation exposure

High energy emissions and relatively large quantities of radioactivity are integral components of radiopharmaceutical manufacturing. The manufacturing facility must comply with the required radiation protection measures (see Section 9). Furthermore, in the light of potentially high radiation exposure of the production staff, the manufacturer should consider investing in automated and/or remote operation equipment. Reducing operator intervention will often reduce radiation exposure and further enhance product quality.