Chapter 44: In-Process Controls

21 CFR 211.110 and Eudralex Volume 4

21 CFR 211.110 “Sampling and Testing of In-process Materials and Drug Products”; Eudralex Volume 4, Part I, Documentation 4, Production 5; and Eudralex Volume 4, Part II, (ICH Q7) 8.3 “Production and In Process Controls” are regulations that require written procedures describing in-process controls, sampling, tests, or examination of in-process materials. These procedures should be subject to review and approval of the quality unit (QU). In-process controls should be established to monitor the production output and to validate the performance of the manufacturing processes that may be responsible for causing variability in the characteristics of in-process materials and the product. In-process monitoring and tests are performed during the manufacture of each batch according to specifications and methods devised during the development phase. Where appropriate, types of in-process controls may include:

• Tablet or capsule weight variation

• Disintegration time

• Adequacy of mixing to assure uniformity and homogeneity

• Dissolution time and rate

• Clarity, completeness, or pH of solutions

Risk management can help identify areas of process weakness, areas of higher risk, and factors that can influence critical quality. Less-stringent in-process controls may be acceptable in early processing, with tighter controls in later processing steps.

Good manufacturing practices (GMP) regulations and quality systems models call for the monitoring of critical processes that may be responsible for causing variability during production. For example, the process steps must be verified by a second person (21 CFR 211.188); process steps can also be performed using a validated computer system. Batch production records must be prepared contemporaneously with each phase of production [21 CFR 211.100(b)]. Although time limits for production can be established, when they are important to the quality of the finished product (21 CFR 211.111), the manufacturer should have the ability to establish production controls using in-process parameters that are based on desired process end points measured using real-time testing or monitoring apparatus (for example, blend until mixed versus blend for 10 minutes). Procedures must be in place to prevent objectionable microorganisms in finished products not required to be sterile and to prevent microbial contamination of finished products purported to be sterile. Sterilization processes must be validated for sterile drugs [21 CFR 211.113(b)].

A quality systems approach calls for the manufacturer to develop procedures that monitor, measure, and analyze the operations (including analytical methods and/or statistical techniques). Procedures should be revisited as needed to refine operational design based on new knowledge. Selected data should be used to evaluate the quality of a process or product and identify opportunities for improvement. Data trends should be continually identified and evaluated to identify potential variances before they become problems, bolster data already collected for the annual review, and facilitate improvement throughout the product life cycle.

Eudralex Volume 4, Part II, (ICH Q7) 8.3 further specifies:

• Critical in-process controls should be documented and approved by the QU.

• Critical process monitoring should be documented and approved by the QU.

• Sampling plans and procedures should be based on scientifically sound practices.

• Sampling should be conducted in such a manner as to prevent contamination of the product.

• Procedures for ensuring the integrity of samples should be established.

• Out-of-specification (OOS) investigations are not normally needed for in-process tests that are performed for the purpose of monitoring and/or adjusting the process.

21 CFR 211.110(b)

In-process specifications should be consistent with final product specifications. They should “be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate.” Testing of in-process samples ensures that in-process and drug product material conforms to specifications.

21 CFR 211.110(c) In-Process Material Testing

In-process materials shall be tested for identity, strength, quality, and purity as appropriate, and approved or rejected by the quality control unit, during the production process (for example, at commencement or completion of significant phases or after storage for long periods).

21 CFR 211.110(d) Rejected In-Process Materials

Rejected in-process materials must be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.

FDA Guidance—Powder Blends and Finished Dosage Units

Guidance was drafted to assist manufacturers in meeting requirements of 21 CFR 211.110 to demonstrate the adequacy of mixing and ensure uniformity of in-process dosage units. This guidance describes the procedures, sampling, and testing that should be performed during development of the product, including performing an assessment of and validating powder mix uniformity, correlating powder mix uniformity with stratified in-process dosage unit data, and correlating stratified in-process samples with final product.

Section VI, “Verification of Manufacturing Criteria,” describes methods for establishing in-process acceptance criteria. The resulting data are used to establish stratified sample locations. At least 10 locations during capsule filling or tablet compression should be identified to represent a batch.

Time Limits

Both 21 CFR 211.111, “Time Limitations on Production,” and European Union (EU) GMP Part II, (ICH Q7) 8.2 “Time Limits” establish time limits to assure the quality of the product, where appropriate. Time limits should be met to ensure the quality of intermediates and product. Deviation from time limits may be acceptable if it does not compromise the quality of the product. Acceptability of deviation must be justified and documented; however, time limits may be inappropriate when processing to a target value, such as pH, or drying to specified values. Manufacturers should have the ability to establish production controls using in-process parameters based on desired end points measured using real-time testing or monitoring equipment.

Microbiological Contamination

Both 21 CFR 211.113, “Control of Microbiological Contamination,” and EU GMP Part II, (ICH Q7) 8.51 and 8.52 state that a company needs written procedures designed to prevent objectionable microorganisms. Operations should be conducted in a manner that prevents contamination by other materials. Handling of active pharmaceutical ingredients (APIs) after purification should include precautions to avoid contamination.

Contamination Control

Eudralex Volume 4, Part I, Production 5.18, and EU GMP Part II, (ICH Q7) 8.5 address contamination control. Residual material carryover into successive batches of the same intermediate or API may be acceptable if there is adequate control. Carryover should not result in carryover of degrades or microbial contamination that can adversely affect the API impurity profile.

21 CFR 211.115 Reprocessing

Written procedures are needed for reprocessing batches that do not conform to standards or specifications. The procedures should include steps to ensure that the reprocessed material conforms to specifications. These procedures need to include review and approval by the QU.

Combination Products

The United States Food and Drug Administration (FDA) does not have GMP regulations for combination products. Each constituent part (drug, device, biologic) is subject to specific GMP regulation if it is marketed separately. For combination products sold as one unit (for example, drug-filled syringes), both sets of regulations are applicable to the whole product after joining. The FDA recommends speaking with the Agency during product development to discuss how best to achieve compliance to regulations for combination products.

Biotechnology Products

Bioreactor fermentation parameters should be specified and monitored. Review of parameter profiles should verify that run parameters are consistent or have an established pattern from batch to batch. Parameters may include growth rate, pH, waste by-product level, viscosity, addition of chemicals, density, mixing, aeration, foaming, and culture purity. Written procedures are needed to assure proper aseptic techniques during cell inoculation and absence of adventitious agents, including criteria for rejecting contaminated runs. The procedures should describe what investigations and corrective actions will be performed in the event that growth parameters exceed established limits.

Once the fermentation process is completed, the desired product is harvested, and if necessary, refolded to restore configurational integrity, and purified. For recovery of intracellular proteins, cells must be disrupted (lysed) after fermentation. After disruption, cellular debris can be removed by centrifugation or filtration. Centrifugation can be open or closed. The adequacy of the environment must be evaluated for open centrifugation. Ultrafiltration is commonly used to remove the desired product from the cell debris. The porosity of the membrane filter is calibrated to a specific molecular weight, allowing molecules below that weight to pass through while retaining molecules above that weight. For recovery of extracellular protein, the primary separation of product from producing organisms is accomplished by centrifugation or membrane filtration. Initial separation methods can be used after centrifugation to concentrate the products.

Further purification steps primarily involve chromatographic methods to remove impurities and bring the product closer to final specifications. Chromatographic separation techniques are multistage separation methods in which the components of a sample are distributed between two phases, one of which is stationary, while the other is mobile. The stationary phase may be a solid or a liquid supported on a solid or a gel. The stationary phase may be packed in a column, spread as a layer, or distributed as a film. The mobile phase may be gaseous or liquid or supercritical fluid. The separation may be based on adsorption, mass distribution (partition), or ion exchange, or may be based on differences in the physicochemical properties of the molecules, such as size, mass, or volume.

The purification process is primarily achieved by one or more column chromatography techniques, such as affinity chromatography, ion-exchange chromatography (IEC), gel filtration, hydrophobic interaction chromatography (HIC), and reverse-phase high-performance (pressure) liquid chromatography (HPLC).

Various types of filtration methods, such as diafiltration, ultrafiltration, and microfiltration, may be used in the purification of vaccine products. Some of the filters used may be single-use and some may be multiuse. The filters are usually placed within a filter-housing apparatus. The criteria used for the evaluation of the column purification should be applied to the filter housings and the multiuse filters.

Viral Clearance

For products derived from cells or source material of human or animal origin, viral inactivation/removal should be performed in accordance with the process in the approved license application. In some manufacturing operations, there will be a specific viral inactivation/removal step; in other operations, viral inactivation/removal will be accomplished by a step or steps in the manufacturing process that are not specifically considered to be viral inactivation/removal steps. In some instances, more than one viral clearance step is used for a given product. Pre- and post-viral inactivation/removal steps (with the exception of products such as albumin, which are virally inactivated in final containers) should be completely separated. Separate areas with a dedicated air-handling unit (AHU) or single-pass air should be used for those steps that occur after viral clearance procedures.

Heat treatment is one method of clearing infectious agents from biologics. Heat treatment is sometimes referred to as pasteurization, and heating equipment such as large water baths may be referred to as pasteurizers. Technically, however, pasteurization is heating at 63 ºC for 30 minutes, which is not sufficient to render plasma derivatives virally inactive.

The parameters specified in the batch record should be achieved such that the validated process for viral inactivation/removal is accomplished. Changes made to the process that do not require submission of a supplement to the Center for Biologics Evaluation and Research (CBER) should be validated.

Inactivation

If the active ingredient is a killed or inactivated version of a live bacteria or virus, the methods for inactivation will have been established and reviewed during product approval. Either heat or chemical treatment may be used for inactivation. The manufacturer should have validated the process and followed the validated procedures during production. All inactivation parameters should be monitored and the appropriate testing performed with acceptable results.

Manufacturing and Aseptic Processing

Aseptic processing in-process controls include environmental monitoring methods, such as surface monitoring, which can be performed with touch plates, swabs, and contact plates, active and passive air monitoring, container weight variation, fill weight, leak testing, established microbial specifications for in-process testing for the lots made, and aseptic connections and transfers. Procedures should be in place for interruption of the fill, should it occur, and for limiting access to controlled and classified areas. Filters should be evaluated before use to assure they meet specifications, and integrity testing should be performed on filters post-fill; results should be in keeping with the manufacturer’s and validated specifications. Written procedures for gowning should be in place and followed.

Some bulk products are held after sterile filtration and before filling. The holding period and storage conditions should have been validated. For lengthy filling operations, time limits should be set and validated to assure that the duration of the fill does not affect the potency of the product and its susceptibility to microbial contamination.

Lyophilization

Lyophilization, or freeze-drying, is a process in which water is removed from a product after it is frozen and placed under a vacuum, allowing the ice to change directly from solid to vapor without passing through a liquid phase. The process consists of three separate, unique, and interdependent processes: freezing, primary drying (sublimation), and secondary drying (desorption). The lyophilization process generally includes dissolving the drug and excipients in a suitable solvent, usually water for injection (WFI), sterilizing the bulk solution by passing it through a 0.22-micron bacteria-retentive filter, filling into individual sterile containers and partially stoppering the containers under aseptic conditions, and transporting the partially stoppered containers to the lyophilizer and loading them into the chamber under aseptic conditions. The solution is frozen by placing the partially stoppered containers on cooled shelves in a freeze-drying chamber or prefreezing in another chamber. A vacuum is applied to the chamber, and the shelves are heated to evaporate the water from the frozen state. The final step is complete stoppering of the vials, usually by hydraulic or screw-rod stoppering mechanisms installed in the lyophilizers.

It is desirable after freezing and during primary drying to hold the drying temperature (in the product) at least 4 ºC to 5 ºC below the eutectic point of the product. The lyophilizer should have the necessary instrumentation to control and record the key process parameters, including shelf, product, and condenser temperature, and chamber and condenser pressure. Other process controls that should be specified in manufacturing procedures are time, temperature, and pressure limits. The monitoring of product temperature is particularly important for those cycles for which there are atypical operating procedures, such as power failures or equipment breakdown.