Susan J. Schniepp is a fellow at Regulatory Compliance Associates, Inc. and a member of Pharmaceutical Technology's Editorial Advisory Board.

Susan J. Schniepp

A.The MBR is the controlling document for product manufacturing. It contains the instructions and specific manufacturing processes needed to produce a particular product. The MBR ensures the ingredients needed to produce a product are correct; added in the correct order; and the mixing, stirring, or other activities used to produce the product are conducted in the correct sequence. For example, the MBR would list an ideal ingredient amount for the product, while the completed batch record would indicate the actual amount used for the individual batch. Batch records are a requirement of 21 

) 211.188, Batch Production and Control Records.

Q. Who is responsible for issuing the batch record to production?

A. Most companies have a document control department that is responsible for issuing the MBR to production. This department may or may not report to the quality department. The most important item to remember about releasing the batch record to manufacturing is that it needs to be tied to an actual production run. The link that ties the MBR to the completed batch record is the lot number assigned to the product being manufactured. Each manufacturing run must have a different lot number for traceability and recall purposes.

Q. Can I release a batch record that has open investigations/deviations associated with it?

 211.22(a), states, “There shall be a quality control unit that shall have the responsibility and authority to approve or reject … drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated” (1). The errors referred to include errors that occur during the manufacturing process. If you are releasing a product that has a batch record associated with an open deviation/investigation then, in my opinion, the “error” has not been thoroughly investigated. The bottom line is, I would not recommend this practice. In my opinion, there is too much risk associated with releasing a product to the field with open investigations or deviations because, if the investigation result indicates the product has not achieved the specified quality attributes, by releasing it you have not only risked patient safety but you are facing a recall situation.

Q. In what order should I review batch record information?

A. I think we need to be clear on what we are discussing when releasing the batch record. It includes a review of the incoming raw materials that include the active ingredient(s), excipients, primary packaging, and labeling. The batch record process should verify these items were properly received, sampled, and put into quarantine until the incoming quality group established their suitability for use. This includes testing of the water that might be used in manufacturing the product. The review should confirm that all the materials used were appropriately discharged using calibrated equipment in a suitable environment and that the manufacturing rooms were properly cleaned and cleared before the start of the batch. The main focus of the picture should be the details of the batch manufacturing itself. Attention needs to be paid to make sure that any deviations during this phase of production have been resolved. It is also important to make sure that operators signed (this could be electronically) in the appropriate places indicating they performed the work. If required, there should also be an indication that another employee or a supervisor witnessed the work. This is particularly important when verifying the right ingredients were discharged to the line to make the right product with the right dosage amount. Many companies use a checklist to make sure all the elements of the master batch record are included in the product batch record. This is an acceptable practice and, when coupled with a thorough review of the contents of those elements, you should confidence in releasing product batches.

Susan J. Schniepp is distinguished fellow for Regulatory Compliance Associates.

When referring to this article, please cite it as S.J. Schniepp, “Frequently Asked Questions about Batch Records,” 

Articles

Susan J. Schniepp, distinguished fellow for Regulatory Compliance Associates, provides simple answers to frequently asked questions regarding batch records.

Frequently Asked Questions about Batch Records

Q: I just attended a meeting where someone talked about the concept of real compliance. Can you explain what they were referring to?

A: This is a great question because I believe there is a difference between regulatory compliance and real compliance. Let’s start with what we mean by regulatory compliance. The current good manufacturing practice (CGMP) regulations for drugs contain minimum requirements for the methods, facilities, and controls used in the manufacturing, processing, labeling, and packaging of drug products.

In the United States, some of the laws are delineated in section 501(a)(2)(B) of the Food, Drug, and Cosmetic Act, which states, “A drug shall be deemed to be adulterated if the methods used in, or the facilities or controls used for, its manufacture, processing, packaging, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this [Act] as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess” (1).

) Part 211 establishes the regulations based on the law. The regulations contained in 21 CFR 211 do not tell you how to specifically meet these regulatory requirements but, rather, tell you what is expected of your quality management system in order to achieve compliance to the regulations. The goal of regulatory compliance is to satisfy the regulations to achieve a satisfactory inspectional outcome.

Real compliance is how a company interprets the regulatory requirements and expectations and applies them to their specific operations. Real compliance is rooted in a commitment to quality at all levels of an organization. A real compliance approach takes a high-level view of quality and allows the organization to put in controls and oversight that helps prevent deviations from occurring. It also provides a better understanding of the impact of a deviation when they do occur during manufacturing. Organizations that adopt a quality-based philosophy (real compliance) minimize the impact when deviations of a serious nature occur. Real compliance is the practical application of a quality management system and how it is integrated in the facility. The goal of real compliance is to achieve a sustainable state of control at the facility based on scientific principles, best practices, and continual improvement efforts. The best way to explain the difference between regulatory compliance and real compliance is to perform a thorough compare-and-contrast exercise.

The regulations clearly require companies to have written procedures that are in the form of standard operating procedures (SOPs). The common language used in 21 

 211 to indicate SOPs are required can be exemplified by 21 

 211.22 “Responsibilities of quality control unit”, which states “(d) The responsibilities and procedures applicable to the quality control unit shall be in writing; such written procedures shall be followed” (2). This type of wording can be found is sections of 21 

 211 governing personnel qualifications, building and facilities, equipment, production and process control, labeling issuance, warehousing procedures, etc. The regulatory requirement is met by having SOPs, but real compliance is met having SOPs that reflect your operations. For example, if you outsource product testing you would not need an SOP on how to investigate out-of-specification (OOS) results because you are not performing that activity. Instead, you might replace it with an SOP describing how you work with your contract test laboratory when they are investigating an OOS result associated with your product. Another example between regulatory compliance and real compliance is just having a complaint department vs. having a complaint department that is manned by employees that understand their responsibilities and are trained in complaint handling best practices. Another comparison demonstrating the difference between regulatory compliance and real compliance is having an organization chart that separates quality and operations vs. having that same organization chart supported by SOPs that demonstrate quality has the responsibility and authority to operate independently.

Here’s a more practical example of regulatory compliance vs. real compliance. US 21 

 211.25(a) requires “Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience or any combination thereof, to enable that person to perform the assigned functions” (2). A regulatory compliance approach would be to offer every employee annual GMP training and document their attendance. A real compliance approach would be to provide effective training to the employees by assessing their comprehension of the material and offering follow-up training as necessary.

Another practical example of regulatory compliance vs. real compliance is examining how a company approaches investigations. A strictly regulatory compliance approach to an investigation results in a firm not determining the true root cause of an issue because the focus is on completing the investigation in a self-imposed time frame instead of focusing on the quality of the investigation. Real compliance organizations focus on determining the true root cause(s) and using that information across their manufacturing facility to drive continuous improvements and prevent recurrence of the deviation that prompted the investigation.

Taking a regulatory compliance only approach to operations may be less expensive in the short term, but in the long term it will most likely result in more expenditure to fix the problems that could have been avoided if a real compliance approach was implemented throughout
the organization.

US Code, Federal Food, Drug, and Cosmetic Act,
Section 501(a)(2)(B).

Susan J. Schniepp is distinguished fellow at Regulatory Compliance Associates.


Volume 46, Number 10
October 2022
Pages 66, 65

When referring to this article, please cite it as S.J. Schniepp, “Regulatory Compliance Versus Real Compliance,” 

Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, addresses the difference between regulatory compliance and real compliance.

Regulatory Compliance Versus Real Compliance

Q. What is a biologics license application (BLA)?

A. BLA is an application sent to FDA that provides information on introducing biological product into interstate commerce. Similar to a new drug application (NDA), a BLA should include the comprehensive product information generated during a development demonstrating safety, purity, and potency of the product including the proposed labeling information to be included in the packaging.All biological products are approved through the BLA pathway, are licensed under Section 351 of the Public Health Service (PHS) Act, and are regulated by the US Food, Drug, and Cosmetic Act (FD&C Act).

Q. What’s the difference between a BLA and an NDA?

A. BLAs and NDAs differ slightly in terms of their application content and submission requirements. The requirements for an NDA are that the drug is proven to be safe and effective, the labeling contains the necessary information, and the manufacturing process does not alter the identity, strength, quality, and purity of the drug. BLAs should also establish that the biological product is safe and potent, but because biologics are manufactured biological living material, the BLA must also provide information that demonstrates the final product does not contain potential extraneous material or viral contamination due to the nature of biologics and the complexities of manufacturing this type of product.

Q. What types of products are filed as BLAs?

A. In Section 351 of the PHS Act, biological products are defined as a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings” (1). FDA regulations and policies have established that
biological products include blood-derived products, vaccines, in vivo diagnostic allergenic products, immunoglobulin products, products containing cells or microorganisms, and most protein products.

Q. What FDA center has oversight of BLAs?

A. While traditional drug products (i.e., small molecules) are regulated by FDA’s Center for Drug Evaluation and Research (CDER), biological products can be regulated by either CDER or the Center for Biologics Evaluation (CBER), depending on the product’s classification.

Q. What is the difference between manufacturing a biological product versus a traditional pharmaceutical product?

A. Traditional drug products are formulated pure chemical substances that are easily analyzed and quantified after manufacturing. Biological products are formulated from living material; therefore, there may be limited ability to identify the active component(s) of a complex biological product.

As a result, these products are often defined by their manufacturing processes. Because changes in the manufacturing process, equipment, or facilities could result in changes in the biological product itself, the production of biologics is monitored by FDA from the early stages to make sure the final product turns out as expected.

Q: How does the failure investigation process differ for biologics?

A. The short answer is there is no process difference when performing deviation investigations for traditional pharmaceutical products versus biological products. The differences lie in the complexity of the manufacturing processes and thus the variables that need to be considered regarding what could have impact on the deviation.

Chemical processes, although sometimes quite complex, often have fewer variables even thoughmany of the categories are the same. For instance, when investigating an unknown impurity in a biological process from a simple oligopeptide fermentation process, the considerations may include fermentation conditions (e.g., time, temperature, oxygen uptake, byproduct production), potential contamination of

reactants including master cell banks and fermentation reagents, equipment integrity, and performance. Further considerations for the downstream purification process variables and the effect of a final configuration (e.g., folding) also need to be considered.

The purpose of performing an investigation into a deviation is to determine why the deviation happened and what its impact was on the product quality. To determine the impact of the deviation on the product quality, it is important to determine the ‘root cause’ of the deviation. The process used in the industry to determine root cause is, of course, the investigation procedure. This procedure, regardless of whether the product you are investigating is biotech or traditional, should require the investigator to review various systems and determine whether they were the cause of the deviation being investigated.

The systems most often reviewed are equipment and machinery, the manufacturing process, the raw materials used in manufacturing, the specifications, the environment, and finally, the operators. This is not to imply that these systems are the only areas you should look at during the investigation but that these are the most probable areas where you will uncover the root cause of the deviation. Each investigation must address the following elements: root cause, impact to the material or product, the immediate correction taken, the corrective action to prevent re-occurrence for specific product/operation, and the preventive action taken to prevent re-occurrences for all products/operations. Once these elements have been investigated, results from the investigation must be documented.

The written narrative should clearly explain what happened, when it happened, and who was involved or observed what happened. The narrative documents the solution and rationale for the root cause that was determined through the investigation process. If you follow your investigation procedure and thoroughly document your results, you should have an acceptable investigation regardless of whether you are manufacturing a traditional product or a biotech product.

1. US Public Health Service Act,Section 351, Part F—Licensing—Biological Products And Clinical Laboratories, Subpart 1—Biological Products Regulation Of Biological Products As Amended Through P.L. 117–159, Enacted June 25, 2022.

When referring to this article, please cite it as. S. J. Schniepp, “Regulatory Applications for Biologics,” 

Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, answers some commonly asked questions about biologics license applications.

Regulatory Applications for Biologics

Q. I work for a small company with a few products in the development phase.I am reviewing several contract development and manufacturing organizations (CDMOs) to determine which one best fits our needs. Can you give me some general guidance on what I should look for when choosing an appropriate partner?

A. Contract manufacturing continues to be one of the fastest growing segments of the pharmaceutical industry. There are many small companies with products in development who do not own manufacturing facilities and must utilize CDMOs to handle their development and manufacturing needs from clinical to commercial product. It is important for both parties to be invested and respectful in the relationship because it is a long-term commitment.

The first step in this relationship is to establish a quality agreement (1–3). If we view the relationship between the two parties as an equation it would be:

where A represents the CDMOs needs, B represents the client needs, C represents the compliance requirements, D represents the regulatory commitments for both parties, while E represents the quality agreement/quality relationship between the two organizations.

Breaking the equation down a bit more, variable: A should take into account the needs of the CDMO including auditing, testing, material sourcing, and any special client needs required to successfully manufacture the product. When defining the audit responsibilities, the CDMO should consider determining the amount of involvement of the client(s) for all audit types.

Variable B represents the client needs and should take into account requirements that might be influenced by development data, regulatory registration commitments, specific sourcing strategies, or any cooperative partnership with other companies. The client should also inform the CDMO of any additional quality agreements that are associated with the manufacturing of the product.

At one point in my career, I worked for a small start-up company which had three quality agreements associated with one product in clinical trials. The three agreements were for three different contract organizations. One CDMO organization was manufacturing the material, another was preforming the release testing, and the final one was performing the product labeling. These complicated relationships should be disclosed to all involved parties so communication between organizations can be optimized, particularly when issues arise.

Variable C represents compliance requirements of the CDMO, which is influenced by multiple customers, regulatory agencies, and standard-setting organizations. Company standard operation procedures (SOPs) (4–6), client SOPs, audit observations, and compendial requirements define this element of our equation. Clients should be aware that CDMOs are usually global in nature and may have obligations to meet compendial requirements of the 

United States Pharmacopeia–National Formulary

) (7). In my opinion, this would be the optimal section to include the communication expectations for regulatory audits conducted either at the CDMO or the client’s business locations. The need for the CDMO to communicate with the client when a regulatory audit is being performed at their facility is evident, but it is equally important that the client communicate with the CDMO when the positions are reversed. This two-way communication is crucial because each organization could be vulnerable based on the audit outcome regardless of where the audit was conducted.

The final variable in this equation is variable D. Variable D considers the regulatory commitments of the client and/or the CDMO. Regulatory commitments are the evolving body of knowledge made up of new or impending regulations or guidelines that may require changes in operations in order to meet the expectations of the new requirements. A CDMO must communicate changes and commitments affecting their quality system to their client and vice versa because these changes may affect regulatory filings.

Finally, the solution to the equation is variable E, which represents the robust quality agreement. The quality agreement should be a living, breathing document that is reviewed and revised as often as needed to clarify both party’s responsibilities and avoid conflict of responsibilities to ensure a successful partnership.

The relationship between the client and the CDMO is important and complex. Both parties need to be knowledgeable on the application and interpretations of the regulations, and they need to work through any opposing opinions to reach an interpretation that works for both parties. A cooperative working relationship can be achieved if each party clearly identifies and communicates their needs through an effective quality agreement.

When referring to this article, please cite it as. S. Schniepp, “Productive Client-CDMO Relationships,” 

Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, discusses the basics for maintaining an acceptable working relationship between a client and their CDMO.

Productive Client-CDMO Relationships

Q. Are compendial methods considered validated?

A. According to the pharmacopoeias, compendial methods are validated—that’s about as simple as it gets. The 

United States Pharmacopeia–National Formulary (USP–NF) 

states “…users of analytical methods described in 

 are not required to validate the accuracy and reliability of these methods but merely verify their suitability under actual conditions of use” (1) The 

) also consider their methods validated. 

states, “The analytical procedures given in an individual monograph have been validated in accordance with accepted scientific practice and recommendations on analytical validation. Unless otherwise stated in individual monograph or in the corresponding general chapter, validation of these procedures by the user is not required” (2). 

 says, “when an analytical procedure is to be newly carried in the 

is to be revised, and when the test carried in the 

 is to be replaced with a new test according to regulations in General Notices, analytical procedures employed for these tests should be validated according to this document” (3). The fact that the supporting validation information for pharmacopeial methods is retained by the compendial authorities and not by the users of the methods does not change the fact that the official methods in these publications are supported by validation information.

This does not mean that the user can just use the methods as is. The methods need to be verified as suitable for use in the user’s laboratory. The USP–NF and the Ph.Eur. describe the requirements for verification in their respective compendia. The

 explicitly require that compendial procedures demonstrate suitability under actual conditions of use. This information can be found in General Chapter, Verification of Compendial Procedures <1226> in the 

(1,2). The European Directorate for the Quality of Medicines (EDQM) stipulates on their website, “When implementing a 

 analytical procedure, the user must assess whether and to what extent its suitability under the actual conditions of use needs to be demonstrated according to relevant monographs, general chapters, and quality systems. In other words, it is the user’s responsibility to transfer the procedure correctly” (4).

Once a monograph has been established and it is accepted that the published method is validated, users of the monograph need to verify that the method is suitable for determining the quality of their product. The purpose of verification is to establish that the official method is reproducible when used by others. The monograph sponsor has already proven the method works for its product with the manufacturer’s analysts using the firm’s equipment in their laboratories. They have already met the basic International Council for Harmonisation (ICH) requirements for reproducibility, repeatability, and intermediate precision. The task for the user of the USP monograph is to prove the published method is reproducible for their company’s product tested by their analysts in their laboratories using their equipment. There is no absolute guidance for verification requirements. Companies must decide for themselves how they will establish the method is verified and suitable for their product. The author does suggest, however, that requirements for test method verification depend on the complexity of the method. Chromatographic methods should, at a minimum, meet the system suitability requirements defined in the official method, but other method parameters, such as accuracy and precision, may be considered. Method performance can be accomplished by using performance characteristics such as blanks in chemistry or un-inoculated media in microbiology, laboratory control samples and spiked samples for chemistry, or positive culture controls for microbiology to assess accuracy. Technique-dependent methodologies should not require verification. These methods include but are not limited to loss on drying, pH, residue on ignition, etc. Technicians should be trained, and their training records maintained, demonstrating their ability to perform the method regardless of the material being tested.

To simplify activities for their analysts, many companies translate monograph instructions into laboratory procedures. Although this practice has its benefits, it can also lead to compliance concerns. To minimize this risk, the author recommends that a baseline comparison be made between the standards and the internal testing documents. For test methods, the comparison does not need to elaborate, but should focus on critical parameters. In addition to precision, accuracy, ruggedness, and robustness, the reader may also want to consider reference standard usage, system suitability requirements, or other parameters that may help establish equivalency to the compendial methods. The criteria listed above should not be considered all-inclusive in establishing that an internal method complies with the official pharmacopeial method as the user may have other requirements to consider for their specific laboratory usage.

 (USP, Rockville, Md., May 2021).
2. EDQM, 

 10th edition, 10.6, General Notices, Section 1.1.2 Compliance with the Ph. Eur., January 2022.
3. JP, 

 18th Edition, June 2021, The MHLW Ministerial Notification No. 220.
4. EDQM, FAQs Home, Do I need validate an analytical procedure that is published in the Ph.Eur.?, 2022, faq.edqm.eu.

Experts Susan J. Schniepp is distinguished fellow for Regulatory Compliance Associates, and Steven J. Lynn is executive vice-president, Pharmaceuticals for Regulatory Compliance Associates.

When referring to this article, please cite it as. S.J. Schniepp and S.J. Lynn, “Verifying Compendial Methods,” 

Experts Susan J. Schniepp, distinguished fellow for Regulatory Compliance Associates, and Steven J. Lynn, executive vice-president, Pharmaceuticals for Regulatory Compliance Associates, discuss the verification of compendial methods.

Verifying Compendial Methods

Q. I work for a small start-up company and have been tasked with writing the quality manual for my company. I have searched but have been unable to find regulations that define what is contained in this document. Can you help?

A. The short answer is there is little guidance on what the actual content of a quality manual should contain. It is clear, when reviewing the regulations, there is an intent to have documentation regarding a company’s overall quality approach. In Europe, 

 Volume 4, Chapter 1, titled Pharmaceutical Quality System, section 1.7, states, “the Pharmaceutical Quality System should be defined and documented. A Quality Manual or equivalent documentation should be established and should contain a description of the Quality Management System including management responsibilities” (1). The United States 

) doesn’t mention a quality manual but does mention a need for a quality policy in the medical device regulations. US 21 

 820.3 states, “Quality policy means the overall intentions and direction of an organization with respect to quality, as established by management with executive responsibility” (2). And in section 21 

 820.20, the regulation states a “Quality policy.Management with executive responsibility shall establish its policy and objectives for, and commitment to, quality. Management with executive responsibility shall ensure that the quality policy is understood, implemented, and maintained at all levels of the organization” (3). The best source for what you should include in your quality manual comes from the International Council for Harmonisation (ICH) in the ICH Q10 document titled Pharmaceutical Quality System (4). Section 1.8 of this document states, “A Quality Manual or equivalent documentation approach should be established and should contain the description of the pharmaceutical quality system. The description should include: (a) The quality policy (see section III (2)). (b) The scope of the pharmaceutical quality system. (c) Identification of the pharmaceutical quality system processes, as well as their sequences, linkages, and interdependencies. Process maps and flow charts can be useful tools to facilitate depicting pharmaceutical quality system processes in a visual manner. (d) Management responsibilities within the pharmaceutical quality system (see section III (2)).” Just to be clear, the quality manual applies to the entire company
and not just the quality department, similar to how the term quality culture is not referring to the culture of the quality department but the entire company’s approach to culture.

Because the quality manual governs the entire company, it is advisable that it be constructed with representatives from various functions in the company. This collaboration helps ensure the overall purpose and scope of the document is representative of the company’s philosophy. A simple purpose statement might say something to the effect, “The quality system described is intended to ensure the facility is compliant with [list regulations] and serves as the basis of the Quality Systems that apply to [list company name], products, and current good manufacturing practice (CGMP) activities.” The scope statement can be just as simple and state something to the effect that the quality systems described apply to all products, personnel, and manufacturing operations to ensure products meet the requirements for safety, identity, strength, and purity.

Another section to consider adding is a section of definitions. It is my experience that each company/facility utilizes their own acronyms. Any special acronyms being used at the facility should be defined in the definitions section along with common acronyms such as CGMP, FDA, EU, SOP, etc. Having a definition section helps everyone (employees, auditors, clients, regulators) understand the overall quality system as it applies to your facility. The next section I would recommend be included is an organizational chart. The organizational chart should demonstrate the reporting hierarchy of the company to demonstrate the independence of the quality organization.

One of the most critical sections to include in your quality manual, in my opinion, is the section on management responsibilities. In this section, you should introduce the company’s management review responsibilities as well as the senior management titles that are responsible for overseeing the pharmaceutical quality system and the management review meetings. The next critical section to include is an overall description of the quality management system in effect at your company. In this section, you can describe your company’s approach to all the applicable systems utilized by your company for planning, documenting, implementing, and monitoring the activities that potentially impact product quality and patient safety. These processes included but are not limited to quality by design, quality risk management, corrective and preventive actions (CAPA), change control management, management of materials, and maintenance of facilities. In describing the quality management system, you should discuss how it relates to manufacturing, facilities and equipment, materials, packaging and labeling, and laboratory controls. If you outsource an activity, you should note that the activity is outsourced and your oversight responsibilities.

The last element of the quality manual is its approval. In my opinion, the quality manual should be agreed to and signed off by representatives from the various departments it governs. The final step in the process is to ensure that everyone, from senior leadership on down, is trained and understands the quality manual and how it relates to their job responsibility. If you follow this simple approach to constructing a quality manual you will have an easy-to-follow, comprehensive document that communicate the company’s commitment to manufacturing safe and effective pharmaceutical products.

 Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Chapter 1, Pharmaceutical Quality System, Jan. 31, 2013.

820.3 Definitions, date updated Jan. 13, 2022.

 820.20 Management Responsibility, date updated
Jan. 13, 2022.

Susan J. Schniepp is distinguished fellow at Regulatory Compliance.


Vol. 46, No. 2
February 2022
Pages: 50, 49

When referring to this article, please cite it as S. Schnipp, “What’s in Your Quality Manual?,” 

Susan J. Schniepp, distinguished fellow at Regulatory Compliance 
Associates, details regulatory requirements for developing a quality manual.