Production and Process Controls in Pharmaceuticals GMP 2020


a.  There shall be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess. Such procedures shall include all requirements in this subpart. These written procedures, including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.

b.  Written production and process control procedures shall be followed in the execution of the various production and process control functions and shall be documented at the time of performance. Any deviation from the written procedures shall be recorded and justified.


With the clear objectives of the current good manufacturing practices (CGMPs), it is perhaps sur- prising that they needed to include such details that there must be written procedures since no one


can be expected to remember everything. Then there is a requirement to follow these written pro- cedures, which seems to state the obvious. However, the FDA has used these requirements to issue repeated inspection observations as FDA483s and warning letters, because some organizations do not have procedures that they need, and even if others do have procedures, they are not followed.

Written standard operating procedures (SOPs) must provide the reader/operator and executor of the responsible steps with clear instructions for performing operational activities and also direct the content of documented evidence that the procedures have been performed. They also provide a basis for the training of personnel; see Chapter 4, “Organization and Personnel and Training”. Procedures are an essential part of quality systems covering all aspects of GMP operations.

The SOP providing detail on the requirements of SOPs, describes the overall procedural require- ments, process, and content for the preparation, approval, and revision. It also includes their dis- tribution and control, as well as the archiving of all GMP documentation and records within a department, all critical for a robust quality system. This SOP defines how to initiate/revise an SOP, provide direction regarding formatting of documents, defines who should review and approve docu- ments, provides the frequency of routine review (often every two to three years), and describes the methodology for issuing and replacement of outdated versions, training, archiving, and destruc- tion. Documents must be uniquely identified, including a version number, as appropriate. When a document has been revised, a system must be in place to prevent the inadvertent use of superseded documents (e.g., only current documentation should be available). The life cycle of a document (creation, distribution, use, archiving, and destruction) must be considered when establishing the control system. Many companies now use automated, validated documentation systems that provide a high level of document control during the review, approval, and distribution processes. Electronic documentation systems provide current versions of SOPs electronically for review by trained, quali- fied personnel. Hard-copy printouts are date-stamped and accompanied by a statement such as “copy only valid for xx/xx/xx” (that day only). Note that the computerized documentation control systems must be validated and their qualification carefully and fully documented. Manual or paper systems are also common, and if planned/executed carefully, the document control system can be effective. Version and distribution control issues (especially forms and attachments), provide addi- tional challenges when developing a manual document control system. Various methodologies are used to compensate for tracking documents via manual systems. The Document Control department is responsible for issuing records and numbered official copies to identifiable recipients. In a manual documentation control system, the use of logbooks to keep track of the transaction is prevalent. The uncontrolled copying of distributed SOPs is not permitted, so the copying may be monitored by printing the document on different colored paper, so that a photocopy is obvious. Borders or unique stamps on the documents is another way of ensuring that only originals have been distributed and to avoid uncontrolled photocopying. Issuance of a unique number to forms provides traceability and accountability, which forms part of document control and is linked to data integrity (restrict- ing the unauthorized duplication of documents); see Chapter 24, “Data Integrity and Fundamental Responsibilities”. Other areas that must be addressed include the storage of critical records, which must be secure and assembled in a defined manner, with their access limited to authorized indi- viduals. Documents must be stored in such a way that they can be easily and efficiently retrieved, especially during an FDA inspection. The storage location must ensure adequate protection from loss, destruction, or damage. Electronic documents and paper records must be adequately protected against misfiling and loss.

A typical SOP format includes sections for the following:






      Description of the Procedure steps

      References: Other Procedures

      Attachments (forms related to the described work process)

      Brief Change History


Operational-specific SOPs should be written by the department and function (e.g., Manufacturing, Packaging, QA) to accurately describe activities and requirements of the task and personnel. Quality systems that are relevant to multiple departments, for example, investigations, corrective and pre- ventive action (CAPA), Change Control, or Annual Product Review require cross-functional SOPs and are usually written by the Quality Unit.

Elements to keep in mind when designing and implementing effective SOPs include preparing an outline of the task to be performed before beginning to write the procedure. A list of important steps that relate to the task will provide a concise and clear summary for the reader. It is important to remember when creating the document that it should be at a level that is easy to understand and that not everyone may have a clear idea of the process that is being described. The use of visual tools, such as process flow charts, symbols, and pictures may also help to communicate clear requirements.

Master production and control records, which define sequential steps for manufacturing and packaging/labeling and their process parameters, are basically SOPs with places to record param- eters, results, settings, weights, etc. As with any SOP, the detail provided needs to be sufficient to ensure that the process will be followed consistently, but not overly complex as to be incomprehen- sible. See Chapter 7, “Records and Reports”.

Every employee engaged in GMP activities must be appropriately trained on all relevant written procedures according to training curriculums. See Chapter 4, “Organization and Personnel”.

Internal quality audits, headed by the Quality Unit, support the identification and evaluation of compliance to written procedures. The report following the summation of the audit provides information pertaining to the scope and purpose of the audit, a summary of the observations found, as well as providing an overall audit outcome (good, satisfactory, action required, or at risk/action required). An executive summary is included in the audit report as well, as it is essential that senior management is aware of the state of compliance of the quality systems/ operations.

External audits, involving personnel from another firm or facility, add an additional layer to compliance assessments. Included in this category are regulatory audits, such as those performed by the Food and Drug Administration (FDA). The FDA in its Compliance Policy Guide “FDA Access to Results of Quality Assurance Program Audits and Inspections (CPG 7151.02)” announced the “FDA will not review or copy reports and records that result from audits and inspections of the writ- ten quality assurance program, including audits conducted under 21 CFR 820.22 and written status reports required by 21 CFR 58.35(b)(4). The intent of the policy is to encourage firms to conduct quality assurance program audits and inspections that are candid and meaningful.” In other words, the FDA encourages the use of internal audits, but it must be kept in mind that in the event of litiga- tion, requests may be made to see such records.

Audits, whether internal or external in nature, are used to assess compliance in regards to the regulatory requirements of CGMPs. CAPAs are used to manage audit observations to ensure adequate implementation of changes by a responsible person by a defined date. Repeated findings of similar noncompliance issues require immediate action to correct and prevent their reoccurrence. The root cause of a non-conformance can be due to a broad range of issues, such as deficient procedures, inadequate training, or insufficient emphasis by management to address a problem. The root cause needs to be identified so that appropriate CAPAs can be assigned. Quality assurance should work with the stakeholders to ensure the corrective action will result in obtaining or restoring systems in a state of control and compliance with regulatory requirements/expectations.

The requirement that execution of the various production and process control functions shall be documented at the time of performance has received increasing regulatory authorities’ attention and observations relating to data integrity in recent years. The significance of this, although not new to FDA-regulated industries, is described in depth in Chapter 24, “Data Integrity and Fundamental Responsibilities”.

From time to time, changes to written procedures are needed and are managed with a document change control process. In order to ensure that the planned change is suitably reviewed, approved, implemented, and documented by appropriate personnel, the management of changes must be adequately controlled. Written procedures detailing the identification, documentation, appropriate review, and approval of changes to fulfill regulatory requirements for change reporting must be in place. A change coordinator routinely monitors the change to facilitate its movement through the process in a timely manner.

Unplanned events or a departure from an approved process or procedure is handled as a deviation or a non-conformance, depending on the event’s criticality. A critical deviation represents a significant fail- ure of a quality system and has a high potential to adversely affect the safety, identity, strength, quality, or purity of materials or products. Immediate action must be taken to isolate a potentially affected process or product involved in a deviation. An investigation must be undertaken whenever there is a failure to comply with relevant documentation or regulatory requirements. The deviation is evalu- ated using a risk management approach, as the outcome of the assessment determines the required response as CAPA actions. The root cause must be identified and an assessment made as to whether the deviation is part of a trend. The Quality Unit will review deviations on an on-going basis, to detect early-stage trends. Unfavorable trends need to be escalated, so that corrective and preventative actions can be put in place to prevent a reoccurrence of the deviation. Adequate time and resources for root cause investigations of deviations, including complaints, must be allocated by management with timely completion and appropriate CAPAs. Incomplete investigations with inadequate root cause(s) create CAPAs that do not address the problems. Ultimately these problems resurface with significant impact to the quality systems and company with ever-increasing attention from regulatory authorities.



Written production and control procedures shall include the following, which are designed to assure that the drug products produced have the identity, strength, quality, and purity they purport or are represented to possess.


a.  The batch shall be formulated with the intent to provide not less than 100% of the labeled or established amount of active ingredient.

b.  Components for drug product manufacturing shall be weighed, measured, or subdivided as appropriate. If a component is removed from the original container to another, the new container shall be identified with the following information:

1.           Component name or item code

2.            Receiving or control number

3.            Weight or measure in new container

4.            Batch for which component was dispensed, including its product name, strength, and lot number

c.   Weighing, measuring, or subdividing operations for components shall be adequately supervised. Each container of component dispensed to manufacturing shall be examined by a second person to assure that:

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1.           The component was released by the quality control unit.

2.            The weight or measure is correct as stated in the batch production records.

3.            The containers are properly identified.

      d.   Each component shall be added to the batch by one person and verified by a second person.


It is important to clarify that the intent of the statement: “The batch shall be formulated with the intent to provide not less than 100% of the labeled or established amount of active ingredient” does not mean that it is required to calculate by assay the exact amount of active ingredient, per batch. Generally, a batch is accepted if analytical results are within specifications, as usually, the results of the assay do not calculate to exactly 100% due to inherent errors (measurements in weighing, analytical methodol- ogy). Some manufacturers may have thought that formulating a product at 98% would save them 2% of the active pharmaceutical ingredient but still produce a product that passed the specification of 97% to 101% of stated amount. A financial incentive not a quality focus. Dispensing is a critical step in the manufacturing process whereby materials, released by the Quality Unit, are measured and transferred for processing for a specific batch as defined in written procedures. Adequate identification of com- ponents is an essential GMP requirement and the labeling of component containers needs to provide sufficient information to ensure traceability. While 211.101(b) specifically requires labeling of new containers, with the component name, control number, weight, and batch to which the component is being dispensed, it is the usual practice that all dispensed materials are labeled accordingly. In addi- tion, while not specified in the regulations, additional information may be added to the label including lot number, dispensing date, and container number. As part of the dispensing process, all secondary containers are to be examined before use to assess the absence of foreign particulates and to ensure the integrity of the container. The requirement that “each container of component dispensed to manufac- turing shall be examined by a second person” (§211.101 [c]) can be interpreted to mean that a second person adequately supervises by examining and ensuring that the component has been released by the Quality Unit, that the weight/measure of the component matches the batch record requirements and that the component has been properly identified. This verification by a second person is needed when the dispensing process is a manual one. In the case where the use of a validated, automated dispens- ing system is in place, a second operator check is not required. Refer to 21 CFR 211.68. Throughout the operation, the materials must be clearly identified, and their status and location must be recorded. This can be done manually by maintaining paper documents or entering the information into a mate- rial management program. Increasingly, data gathering is being accomplished using bar codes and scanners and radio frequency (RF) interfaces. The data gathered from these systems can be entered automatically into the inventory control system while increasing accuracy. The same logic applies to the need for a second check when verifying components in production. Once again, if the addition of components is manual, a second human check is required, while the use of a validated automated system will permit a single operator to perform the dispensing operation.



Actual yields and percentages of theoretical yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product. Such calculations shall be performed by one person and independently verified by a second person.


Theoretical yield defined in Section 210.3(b)(17) is defined as the maximum quantity that could be produced, based on the quantities of components assigned to a batch, in the absence of any loss or error in production.

All materials assigned to a batch need to be compared to the actual yields at appropriate pro- cess steps. On the basis of historical, validated data, an acceptable range for the actual yield at each appropriate stage can be calculated. By assigning an acceptable range at various stages of the process, process control trends can be generated. In addition to assessing the theoretical yield, cal- culating the acceptable product yield provides a better tool for evaluating process changes. Although different lots of a batch could have identical theoretical yields, their acceptable product yield could vary widely, as for example in the case of waste. Without further examination of the acceptable product yield percentages, investigation into potential problems within a process could theoretically be overlooked.

As required by the GMP regulations, yield calculations involve reporting the following data/ calculations at each appropriate phase:


      Actual yield (kg)

      % of theoretical yield = (actual yield/theoretical starting quantity) × 100

      While the percent acceptable product yield is not a GMP requirement, it provides addi- tional information to alert personnel of potential process control issues

      % acceptable product yield = ([acceptable product]/theoretical yield) × 100.


a.  All compounding and storage containers, processing lines, and major equipment used during the production of a batch of a drug product shall be properly identified at all times to indicate their contents and, when necessary, the phase of processing of the batch.


This requirement is clear in requiring identification and traceability during production process. Status labels or tags must always be attached to equipment, process lines, and con- tainers and provide information regarding its contents (product/material, batch number), the status of cleanliness (to be cleaned/clean), and process stage (granulation). Multiple pieces of equipment that are cleaned and used in a train within a suite may have a status tag gener- ated for the room, rather than for each individual piece of equipment. The use of equipment logbooks, in addition to status tags, can provide a permanent record and additional support information (type of cleaning performed, time/date of cleaning, personnel responsible). This information is needed in cases whereby a batch or process is under investigation.

In-process materials are required to be labeled with the product, batch number, and stage of processing, and if multiple containers are used, sequentially numbered.


b.  Major equipment shall be identified by a distinctive identification number or code that shall be recorded in the batch production record to show the specific equipment used in the manufacture of each batch of a drug product. In cases where only one of a particular type of equipment exists in a manufacturing facility, the name of the equipment may be used in lieu of a distinctive identification number or code.


The intent of this subsection is to allow identification and traceability of equipment involved in the production process. This is particularly important where several different pieces of the same equipment are used for the process, as the same type of equipment does not ensure that they will all process identically. In the case where there is only one piece of equipment, it is sufficient to record the name of the equipment in the batch record.



a.  To assure batch uniformity and integrity of drug products, written procedures shall be established and followed, which describe the in-process controls, and tests or examinations to be conducted on appropriate samples of in-process materials of each batch. Such control procedures shall be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such con- trol procedures shall include, but are not limited to, the following, where appropriate:

1.           Tablet or capsule weight variation

2.            Disintegration time

3.            Adequacy of mixing to assure uniformity and homogeneity

4.            Dissolution time and rate

5.            Clarity, completeness, or pH of solutions

   b.  Valid in-process specifications for such characteristics shall be consistent with drug prod- uct final specifications and shall be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate. Examination and testing samples shall assure that the drug product and in-process material conform to specifications.

c.  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.


Statistically sound sampling criteria must be used to determine the variability of key product parameters. These tools should be used in all stages of the production system. A documented sampling plan, approved by the Quality Unit needs to be in place and an acceptable quality level (AQL) is assigned to each defect type to ensure the safety and quality as established by product performance and quality requirements. Samples are representative of the whole, and sample locations or time points in the process are described or determined by the most stressed part of the process (e.g., beginning or end of process).

Process validation is performed to “establish(ed) and monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.” The requirements for this validation are set out in 21 CFR Part 211.100 (a) which the FDA calls the regulatory “foundation for process validation.” Manufacturers are required to have production and process-controls procedures in place that are “designed to assure” drug products have a certain level of quality and that their products are manufactured safely, effectively, and purely.



In January 2011, FDA revised its guidance for industry on Process Validation: General Principles and Practices. The guidance aligned process-validation activities with the product life-cycle con- cept and with existing harmonized guidelines. The guidance now defines process validation as “… the collection and evaluation of data, from process design through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality products.” The activities involved in process validation occur over the entire life cycle of a product and can be divided into three (3) distinct stages.


Stage in Process design

The commercial manufacturing processes are defined during Stage I, based on knowledge gained through development of the process, site transfer, and scale-up activities. Process knowledge and understanding lead to the development of appropriate process controls, which can be used to address variability in the process. It is essential to understand the sources and impact of the variation to be able to detect the degree of variation in the process. Control of the variation should be in proportion to the risk that it potentially presents to the process or product. The information gathered during Stage I will be incorporated into the designed manufacturing process and will then be confirmed Process design and development represents the first stage of the process validation life cycle. In the case of product transfer and scale-up, this stage begins during the planning of a site transfer and continues through the verification of the manufacturing process at the transfer location. Site transfer and scale-up activities must be well defined and documented. They should be based on knowledge gained from other similar processes and products as well as from development reports generated by the originating site. Thorough documentation is needed in order to fully understand the process and all potential factors, which may impact it.

Process steps and operating parameters are defined during the process design stage. The impact of process parameters and material interactions on process performance and product quality must be evaluated. Initial identification of Critical Process Parameters (CPPs) and material attributes are defined based on data obtained during development.

The functionality and limitations of commercial manufacturing equipment must also be considered in the process design stage. Other factors to consider include the possible contribution to variability that may be caused by different production lots, production operators, environmental conditions, and measurement systems in the production setting. Usually all the input variability that is typical of commercial production is not known at this stage. An assessment of the identified CPPs and material attributes must be performed at each scale-up step through commercial manufacturing in order to estimate process variability.

GMP documents need to be defined before the process performance qualification (Stage II) can start. A defined target profile for the product will have been identified, with target settings, and will be adhered to in order to show process consistency. A detailed assessment of product quality attributes and process parameters to establish specifications will have been determined. Control limits and ranges will have been established and verified during scale-up activities. Documentation including process flow diagrams with information regarding critical set points, inputs, and the expected outputs will be established. A risk assessment to select critical process steps and parameters and to assess process robustness and process risk will have been performed, following local procedures or guidance. Master manufacturing documentation will have been drafted by the process owner for use during commercial-scale process performance qualification batches.


Stage ii—Process Performance Qualification

During this stage, the process design is evaluated to determine if it is capable of reproducible results during commercial manufacturing. There are numerous prerequisite activities that must occur prior to the actual process qualification. Process performance qualification, which is equivalent to process validation, must be done according to a preapproved protocol, and sampling is to be performed to a higher level than the normal quality sampling of a batch. The approach to this stage should be based on an understanding of the process and of sound scientific basis. The completion of Stage II is the equivalent of reaching a “validated state” for the process.


Number of Validation Batches

The number of batches required for validation must be scientifically justified, using statistical measures to achieve adequate assurance. Factors that affect the number of batches required include the complexity of the process and the level of process variability.

New products for launch or transferred from another site may be validated with a minimum of three batches or via a matrix approach. Other validated products may be produced on the equipment in between the validation batches for the new product. Until the three consecutive validation batches (or then number of batches defined in the protocol have been completed), no additional batches of the new product shall be manufactured.

If a validation study is required involving a product with multiple dosage strengths, product sizes, and/or batch sizes, a bracketing or matrixing approach may be utilized to address the entire product family. If this approach is selected, it must be justified, documented, and approved.

Results from Stage II verifications should include a successful process validation (PV) with an approved PV report and confirmation of all proposed critical material attributes, critical quality attributes, critical process parameters, and in-process controls. Risk assessments and process validation plans shall be updated as applicable. Process validation-related documentation, such as SOPs or master batch records (MBRs), which were in draft form prior to the execution of the PV will be revised, approved, and trained prior to release of the process.


Stage iii—continued Process verification

Continued Process Verification provides assurance that the manufacturing processes are in a continued state of control during routine commercial production. A program is established to collect and analyze product and critical process data on a regular basis. Inter- and intra-batch variability must be evaluated in order to be able to monitor process controls. Monitoring and sampling needs to be performed at the same level as during Stage II until there is sufficient data to provide a level of confidence that the process is in control and statistically-significant variability estimates can be generated. At that time, monitoring can be adjusted based on data collected.

Annual review of validation status is also an important part of this process. Review of deviations, investigation results, product failures, complaints, and other product performance and quality indicators shall be included as a component of the Continued Process Verification program.

Annual Monitoring/Validation Batch

The validation status of a drug product is regularly updated by performing at least one annual monitoring/validation batch, in alignment with the annual product review (APR) cycle, as part of continuous process validation. If the process has been revalidated during that year or the product was not produced within that time period, the annual monitoring/validation batch is not required. The annual monitoring/validation batch must be included in the stability program.

If significant deficiencies are identified during review of the current validation package, the need for complete revalidation must be assessed.

Change Control and Revalidation

All changes to equipment, systems, utilities, processes, materials, specifications, methods, and procedures must be assessed for their impact on the validated state and are subject to the change control process.

A process may require revalidation based on review of Continued Process Verification data (e.g., due to an increase in variability) or due to a change in the process. When a process change is proposed, the extent of revalidation required, if any, must be based on an assessment of the impact of the change to the critical quality elements of the process. At a minimum, the following must be considered:


      Change of manufacturing or supporting processes

      Changes in the master manufacturing formula, procedure, or batch size

      Changes in validated ranges of process parameters

      Raw materials, specifications, grade, reference standards, or test methods

      Changes to container closure system

      Changes to equipment, instrumentation, or computerized systems or their maintenance

      Changes to facilities or utilities

      Changes to the quality system, including deviations, investigation results, product failures, complaints, or other quality indicators

      Trends, for example, from Continued Process Verification and Annual Product Reviews


Revalidation covers either the entire scope of the original validation or is limited to specific process parameters or steps, depending on the justification described in a validation protocol. The impact of limiting the scope of revalidation with respect to its impact on other steps should be carefully assessed. Process assessment will include a review of the current process and its data, all historic validation and revalidation activities, and current issues, as applicable. The process assessment report will summarize recommendations for process improvements, if required, and further steps to be taken.

Process Validation Approach

There are three possible approaches to process validation: prospective, concurrent, and retrospective. Prospective validation must be applied to new processes, including existing, approved processes transferred from other sites, and process, material, or equipment changes, under change control, as documented through the change control process. Validation batches must be at the intended commercial scale, utilizing final process parameters on equipment to be used for commercial production. Prospective validation activities, including approval of final reports, must be complete prior to

commercial distribution of the final product.

Concurrent validation involves release of product for commercial distribution prior to the completion of all validation activities. This approach is acceptable only in exceptional cases such as infrequent production (i.e., one or two batches per year) or established processes that have not been validated to current standards. The rationale/justification for the approach must be documented and approved by Quality in advance. Batches may be released after approval of an interim report. Concurrent validation may also be used for revalidation of legacy products where there has been no change from the current process.

Retrospective validation involves the review of historical data and includes all batches made during a review period. This approach is not acceptable for the validation of new products. New processes and changes to existing processes may not be retrospectively validated. Retrospective validations for existing (legacy) processes must be replaced with prospective validation studies in order to meet current standards and expectations.



When appropriate, time limits for the completion of each phase of production shall be established to assure the quality of the drug product. Deviation from established time limits may be accept- able if such deviation does not compromise the quality of the drug product. Such deviation shall be justified and documented.


The main purpose of this regulation is to indicate that products need to remain stable before processing to the next stage. Maximum allowable hold times are established as part of a pilot plant study or validation exercise for starting materials, intermediates, and bulk and finished products to ensure materials are not adversely affected by in-process or storage conditions. Hold-time studies establish the time limits for maintaining materials during different stages of production to ensure the quality of the product does not deteriorate over time. The containers used to hold the hold-time samples need to simulate the containers that are used in production, and in the case of bulk product, the head- space needs to be in proportion to the bulk product stored during manufacturing. The environmental conditions of the hold-time studies should reflect the actual manufacturing conditions being tested. Products that are undergoing hold-time studies should also be put up to long-term stability testing.

The determination of maximum hold-time limits is critical where product is sensitive to environmental conditions, as an example: moisture, oxidation, or microbial attack. In these cases, it is critical that the maximum allowable hold times be determined and clearly specified in the manufacturing batch records. The batch record will then provide evidence through the recording of date and time by the operator that the product has not exceeded its time limitations as determined in the validation study. It is acceptable for validated time limits to be revisited and extended, as long as the subsequent validation studies show that the product has remained stable, with no adverse impact to the quality, safety, or efficacy of the drug product.



a.  Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.


For most products other than injections and eye preparations, there is no need for sterility. For these products, the presence of microorganisms could still constitute a problem since certain microorganisms are associated with human illness and must be absent. For example, oral suspensions and solutions should be tested for freedom from Escherichia coli; products for topical application should be tested for freedom from Pseudomonas aeruginosa and Staphylococcus aureus.

Some products may also be prone to microbial degradation resulting in loss of active ingredient or breakdown in physical characteristics, such as emulsions. In such cases, it may be necessary to have a specification for total viable microorganisms.

The USP 29 General Information Chapter <1111> Microbiological Examination

of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use addresses total plate count criteria for bacteria and yeasts/molds. In addition, it discusses evaluation of other microorganisms recovered in terms of the following:


      The use of the product (e.g., route of administration)

      The nature of the product as it relates to supporting growth

      The method of application

      The intended recipient (e.g., neonates, infants, the debilitated)

      The use of immunosuppressive agents

      The presence of disease, wounds, organ damage


The presence of certain microorganisms in nonsterile preparations may have the potential to reduce or even inactivate the therapeutic activity of the product and has a potential to adversely affect the health of the patient.

Chapter <1111> gives examples of total plate count limits as well as the absence of

certain microorganisms based on route of administration. For example, as taken from Table 6.1 in Acceptance Criteria for Microbiological Quality of Nonsterile Dosage Forms, the total plate count criteria for nonaqueous preparations for oral use are less stringent than those for oromucosal use products.

The procedures and conditions required to assure adequate microbial control will vary according to the specific products but are likely to include some, or all, of the following:


1.           Microbial monitoring of potentially susceptible raw materials. This may require special negotiation with the supplier if a microbiological specification is not a normal requirement for his other customers. Current practices involve the setting of microbial specifications for materials of natural (animal, vegetable, or mineral) origin, those likely to support microbial growth, and materials to be used in product formulations with rigorous microbial specifications, such as injections.

2.            Equipment sanitation procedures that have been proven effective, especially for any specific known deleterious or objectionable microorganisms.

3.            Processing conditions that minimize the potential for microbial growth.

4.            Environmental control including covers over equipment; laminar flow at susceptible points, wearing of protective clothing such as gloves and masks, and clearing filling lines at breaks.

5.            Formulations to include preservatives.


Production and Process Controls

Although there may be a need for limits for liquid products, especially aqueous products, there would seem to be less value for solid oral dosage products. Microbial contamination has not been a problem except for products involving materials of natural origin. The USP General Information Chapter <1112> Application of Water Activity Determination to Nonsterile Pharmaceutical Products addresses water activity in relationship to Microbial Limit Testing strategies. This chapter notes that determination of water activity of nonsterile pharmaceutical dosage forms aids the decision-making process regarding optimized product formulations, susceptibility to microbial contamination, frequency of microbial limit testing, etc. It points out that nonaqueous liquids and dry solid dosage forms will not support microbial growth due to low water activity.


b.  Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed. Such procedures shall include validation of any sterilization process.


Sterile products are manufactured using either terminal sterilization or aseptic processing. The level of sterility assurance is significantly higher with terminal sterilization; autoclaving at 121°C can result in a 10−6 microbial survivor probability, whereas aseptic processing tends to result in the order of 10−3. Because of these significant differences in assurance levels, terminal sterilization should be the method of choice. Some products cannot withstand the temperature conditions of autoclaving, the ingredients may be heat labile or the package may be physically affected by the pressure changes (e.g., prefilled syringes), and aseptic processing may then be necessary. A useful compromise situation is a combination of aseptic processing with some level of heat treatment that could effectively kill off vegetative organisms without adversely affecting chemical stability or physical integrity.

The subject of aseptic processing versus heat sterilization or the compromise of aseptic plus some heat treatment can be very complex, especially for those products that have some degree of heat lability. The possible permutations of temperature and time are almost limitless. Also, the relative benefits/disadvantages of aseptic processing with low levels of degradants and some heat treatment with higher levels of sterility assurance but also higher levels of degradants need to be evaluated.

Whichever process is used, the probability of having a nonsterile unit will be extremely low. Consequently, assurance of sterility cannot be demonstrated by testing a limited number of samples. For example, when sterility testing 10 units, lots with 0.1% contaminated units could be passed as sterile 99 out of 100 times. Increasing the sample size to 100 still leaves a 91% chance of passing a contaminated batch. Also, if the sample size is increased, the potential for false positives also increases. This then places a greater emphasis on the need to validate the sterilization process and to ensure that the defined process is followed for every batch of product. The key parameters to be evaluated for the different types of sterilization are outlined below; whichever process is used, the same basic steps outlined previously for process validation are also to be included: product/ process design, equipment qualification, services qualification, process performance, and revalidation. Validation of heat sterilization (dry heat or autoclave) includes:


   1.     He  at distribution within the empty sterilization chamber

   2.      Heat penetration within the units of product for the various loading cycles to be used

   3.     Lethality calculations based on the known numbers of resistant bacteria or spores killed, usually Geobacillus stearothermophilus spores placed in units that receive the least heat treatment

4.     Bioburden data showing the numbers and types of organisms, with particular reference to resistivity, likely to result from the components and the process prior to sterilization

5.     Perform studies outside the ranges of conditions that will routinely be used for sterilization cycles



1.     Treatments of product components and processing equipment to remove particulate matter, sterilize, and depyrogenate are critical to effective aseptic processing. This include ampoules, vials, stoppers, filters, intermediate storage vessels, tubing, filling equipment, gowns, masks, and gloves. The processes for each of these must be validated.

        2.      Environmental qualifications must include:

a.     Air quality. At the point of use (e.g., filling), air should be supplied by high-efficiency particulate air (HEPA)-filtered laminar flow air at about 90 feet per minute and with a pressure differential to adjacent areas of different classification of at least 10–15 Pa with doors closed. Nonviable particle counts should be less than 100 per cubic foot equal to or larger than 0.5 μm (Class 100/grade A or ISO 5); viable particles should be not more than one colony forming unit per 10 cubic feet. Where an aseptic processing room is adjacent to an unclassified room, an overpressure of at least 12.5 Pa from the aseptic processing room should be maintained according to the 2004 FDA Guidance for Industry—Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice.

Away from the critical filling area, where product is not exposed to the environment, less stringent requirements are necessary but must still be controlled in order to minimize the bioburden load. The Class 100,000 (ISO 8) (not more than 100,000 particles per 0.5 μm or larger and not more than 25 colony-forming units per 10 cubic feet) should be adequate. Air filter integrity and efficiency testing should be included.

b.      People. The presence of people in an area or room will have an impact on air quality. The validation study should include the maximum number of people expected to be present at any time during the process. Other people-related activities to be examined would be training programs, especially with respect to microbiological understanding, aseptic techniques, and gowning techniques. The effectiveness of these techniques can be evaluated by the use of swabs, contact plates, and touch plates.

c.      Time limitations. Liquid preparations and wet components are prone to microbial multiplication, including the possibility of microorganisms passing through filters. Maximum time frames for key steps need to be confirmed.

d.      Product filtration. The filtration system used to “sterilize” the drug product, usually

0.22 μm, should be challenged using a suitable small organism, usually Brevundimonas diminuta. The number of organisms used in the challenge will be in excess of the maximum bioburden levels measured in unfiltered solutions.

e.      Media fills. The overall effectiveness of the aseptic process is then validated using liquid media fills.

1.           Initially, three media fills are considered desirable.

2.            According to the 2004 FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice, the starting point for a media fill run size is 5000 to 10,000 units. For production sizes under 5000, the number of units should be at least equal to the batch size.

3.           Each shift and each employee used for aseptic processing should be included in the media fills.

4.           According to the guidance, the recommended criteria for assessing the state of aseptic line control are as follows:

       When filling fewer than 5000 units, no contaminated units should be detected.

       One (1) contaminated unit is considered the cause for revalidation, follow- ing an investigation.

       When filling from 5000 to 10,000 units:

       One (1) contaminated unit should result in an investigation, including con- sideration of a repeat media fill.

       Two (2) contaminated units are considered the cause for revalidation, fol- lowing investigation.

       When filling more than 10,000 units:

       One (1) contaminated unit should result in an investigation.

       Two (2) contaminated units are considered the cause for revalidation, fol- lowing investigation.

f.      Revalidation. As with any process, revalidation should be considered whenever there is a change in the product, components, process, facility, equipment, or people. Additionally, since the aseptic process is so people dependent, regular revalidation is essential. This routine revalidation should normally be performed every six months on each different type of process and for each shift; every operator should be included in a revalidation at least every 12 months.


The routinely collected data on bioburden levels and environmental conditions will also serve to confirm that the process is being maintained under control.

The greatest potential source of microbial contamination in an aseptic environment is people. The interaction of people and process is also not consistent. One way to significantly minimize this potential microbial exposure and variability is to separate the people from the process. Newer aseptic installations and upgrades are introducing barrier technology. This technology maintains the environmental conditions around the product at Class 100 or better while allowing personnel access only by way of glove ports. Consequently, there is no direct interaction of people and process. This approach greatly enhances the potential for sterility assurance—from about 10–3 to 10–5 or 10–6.


The 2004 FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing— Current Good Manufacturing Practice discusses various aspects of maintenance, design, and monitoring of Aseptic Processing Isolators in Appendix A and Blow-Fill-Seal Technology in Appendix B.

Another benefit of the use of barrier technology is that the high-quality air needs to be supplied only to the product operational area and not to the entire room.



This process is used for the sterilization of components but not for products. Because of the inherent health hazards associated with the use of ethylene oxide, its use is diminishing. Key parameters to be included in the validation study include:


  1.     Distribution of temperature, ethylene oxide, and humidity in the sterilization chamber

  2.      Penetration of gas and moisture of the material to be sterilized

  3.     Lethality calculations based on the known numbers of resistant bacteria or spores killed

  4.     Removal of ethylene oxide and ethylene glycol residues



Gamma radiation using Cobalt-60 is used for the sanitization and sterilization of many pharmaceutical raw materials and products. Usually, these are solids or nonaqueous preparations because water when irradiated generates free radicals, which tend to cause degradation. Gamma radiation is easy to use since time is the only variable once dosage has been established. There is also some evidence that gamma irradiation can reduce endotoxin levels.

The validation of a gamma irradiation sterilization process involves three stages.


1.     Product qualification evaluates the impact of radiation on the product. Three levels of radiation may be determined: (i) maximum tolerated level—the highest dose that fails to induce an unacceptable change in the product; (ii) maximum process dose—based on the defined sterilizing dose—to be applied and the highest level of exposure in any unit of product; (iii) minimum process dose—the opposite of (ii). The optimum situation is for maximum and minimum process values to be close but significantly lower than the maxi- mum tolerated level.

Assessment of impact must use real-time stability studies, since accelerated conditions may result in more rapid degeneration of free radicals and give an impression of greater stability.

2.      Equipment qualification is normally performed by the operator of the facility and should address design, installation, operation, and maintenance.

  3.     Process qualification should include:

a.      Sterilization approach, of which there are three: (i) overkill, which usually involves radiation doses in excess of 25 kGy and can only be used for products that are radiation stable; (ii) bioburden, which relies on a lower level of radiation based on the known and constant bioburden of the product; and (iii) species-specific, which uses an even lower radiation dosage and is particularly useful for products with a low, nonresistant bioburden such as pharmaceuticals.

b.      Dose distribution in the loads using well-defined loading patterns.

c.      Biological challenge using Bacillus pumilis.

d.      Cycle interruption studies.


a.  Written procedures shall be established and followed prescribing a system for reprocessing batches that do not conform to standards or specifications, and the steps to be taken to ensure that the reprocessed batches will conform to all established standards, specifications, and characteristics.

b.  Reprocessing shall not be performed without the review and approval of the quality control unit.


Reprocessing is defined as the introduction of a product or material back into a manufacturing process. This is an exception in a process and must not be conducted without first formally investigating the issue. The quality system, which defines reprocessing steps, must be defined in approved written procedures. If a proposal has been made to reprocess a material, the decision must be documented by the Quality Unit in a deviation report and an investigation performed. The reprocessing material cannot be released until the investigation has been completed as defined in the SOP and approved. Reprocessed material must be supported by process validation and stability, as well as being per- mitted by the product license. If there is no existing supporting stability data, the batch must be put on stability testing prior to release. Release testing must be performed for reprocessed products and the need for additional testing must be considered as the normal release standards will not necessarily be sufficiently robust to evaluate the reprocessed batch.

If the reprocessing becomes a common recurrence, then the adequacy of the manufacturing process needs to be assessed and appropriate improvements be taken.



      The processes used to manufacture your (b)(4) drug products have not been shown to be consistent and reliable, and consequently batches of your drug products are likely to significantly vary in strength, quality, and purity.

      FDA collected samples of your (b)(4) batch #(b)(4) at the port of entry. FDA laboratory analysis found that your (b)(4) did not contain any of the labeled active ingredient, (b)(4). FDA denied entry of the shipment accordingly and notified your customer, (b)(4), which filed a complaint with you.

      Your subsequent investigation into the customer complaint for batch #(b)(4) revealed that, during (b)(4) of components, you added the wrong ingredient, (b)(4), instead of the active ingredient.

      No restricted access to the microbial identification instrument. Further, you lacked restricted access to the external hard drive used for backup of this instrument. All users could delete or modify files. In your response, you commit to limit access to the system and external hard drive. However, your response is inadequate because you did not provide a retrospective risk assessment of the impact and scope of inadequate system controls at your firm.

      Your master batch records lacked a statement of theoretical yield, percentage of theoretical yield, and statements of limits beyond which an investigation is required. Without calculating theoretical yield, you may be missing important indications of possible error throughout your manufacturing process.

      In January 2013, multiple in-process and finished product batches of xxxxxx USP failed to meet release specification for (b)(4). Failure to meet (b)(4) specifications may reduce the effectiveness of products administered as nasal sprays. You rejected these batches and cor- responding finished products and undertook an investigation into the (b)(4) failures. Your investigations (b)(4) and (b)(4) stated that “the root cause can be attributed to the raw mate- rial... (b)(4)...” but offered no further explanation for the failures and did not specify the basis for your conclusion.

      Following these investigations, you began manufacturing (b)(4). However, you have never revalidated your manufacturing process to account for the variability in your finished product that you initially attributed to (b)(4).

      Bulk (b)(4) used in solid (b)(4) dosage form manufacturing were held for excessive periods during commercial batch manufacturing without adequate hold-time studies or scientific jus- tification. For example, in many instances, bulk (b)(4) for multiple drug products were held for longer than (b)(4), including some held significantly beyond (b)(4). Despite these exces- sive (b)(4) hold times, you released the (b)(4) for (b)(4), and rarely placed the finished product batches in your stability program.

      Your smoke studies do not support your assertion that you maintain unidirectional airflow for all aseptic operations. At times, the smoke volume was too low to accurately demonstrate airflow. You did not inject the smoke in areas that showed the effects of operator interventions on the unidirectional air stream. These smoke studies do not demonstrate that your line is designed to prevent microbiological contamination, or to provide high assurance of product sterility.

      There were no SOPs for the QA investigations of product failures, laboratory failure investi- gations, and stability investigations.




      FDA Guidance for Industry: Q8(2) Pharmaceutical Development. Rockville, MD, U.S. Dept. of Health and Human Services, May 2009.

      FDA Guidance for Industry: Q8, Q9, and Q10 Questions and Answers (R4), November 2011.

      FDA Guideline on General Principles of Process Validation, January 2011.

      FDA Draft Guidance for Industry: Powder Blends and Finished Dosage Units—Stratified In-Process Dosage Unit Sampling and Assessment, November 2003.

      FDA Guideline on Sterile Drug Products Produced by Aseptic Processing, September 2004.

      Agalloco JP, Carlton FJ. Validation of Pharmaceutical Processes Sterile Products. 2nd ed. 1998.

      Wachter AH, Nash RA. Pharmaceutical Process Validation. 3rd ed. New York, Marcel Dekker, 2003.

      Subchapter 490 Validation Sec. 490.100 Process Validation Requirements for Drug Products Subject to Pre-Market Approval (CPG7132C.08) Issued: 8/30/93, Revised: 03/12/2004.

      Subchapter 420 Compendial/Test Requirements Sec. 420.100 Adulteration of Drugs Under Section 501(B) And 501(C) of The Act [Direct Reference Seizure Authority for Adulterated Drugs Under Section 501(B)] (CPG 7132A.O3) Issued: 6/20/85, Reissued: 9/4/87, 3/95.

      PIC/S Recommendation on the Validation of Aseptic Processes, January 2011.

      ISO 13408-1:2008 Aseptic processing of health-care products—Part 1: General require- ments (parts 2–8 also deal with aseptic processing).

      PDA Technical Report No. 28 Process Simulation Testing for Sterile Bulk Pharmaceutical Chemicals, January 2006.